MXPA97008032A - Derivatives of indol-3-carbonyl and indol 3-sulfonyl as antagonists of the plaqu activator factor - Google Patents
Derivatives of indol-3-carbonyl and indol 3-sulfonyl as antagonists of the plaqu activator factorInfo
- Publication number
- MXPA97008032A MXPA97008032A MXPA/A/1997/008032A MX9708032A MXPA97008032A MX PA97008032 A MXPA97008032 A MX PA97008032A MX 9708032 A MX9708032 A MX 9708032A MX PA97008032 A MXPA97008032 A MX PA97008032A
- Authority
- MX
- Mexico
- Prior art keywords
- carbon atoms
- indole
- methylimidazo
- pyrid
- alkyl
- Prior art date
Links
- SIKJAQJRHWYJAI-UHFFFAOYSA-N indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims description 162
- -1 indol-3-carbonyl Chemical class 0.000 title claims description 98
- 230000003042 antagnostic Effects 0.000 title abstract description 6
- 239000005557 antagonist Substances 0.000 title abstract description 5
- 239000012190 activator Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 100
- 108010003541 Platelet Activating Factor Proteins 0.000 claims abstract description 28
- 239000011780 sodium chloride Substances 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 122
- 125000000217 alkyl group Chemical group 0.000 claims description 79
- 239000002253 acid Substances 0.000 claims description 70
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 63
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 58
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 claims description 49
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 46
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 40
- 125000003545 alkoxy group Chemical group 0.000 claims description 35
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 22
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 12
- 125000001188 haloalkyl group Chemical group 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 230000002401 inhibitory effect Effects 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 125000001589 carboacyl group Chemical group 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- FHUKMQAWBVIQBH-UHFFFAOYSA-N indole-1,4-dicarboxylic acid Chemical compound OC(=O)C1=CC=CC2=C1C=CN2C(O)=O FHUKMQAWBVIQBH-UHFFFAOYSA-N 0.000 claims description 7
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 6
- UTWGRMYWDUMKNY-UHFFFAOYSA-N indole-1-carboxylic acid Chemical compound C1=CC=C2N(C(=O)O)C=CC2=C1 UTWGRMYWDUMKNY-UHFFFAOYSA-N 0.000 claims description 6
- 230000001404 mediated Effects 0.000 claims description 6
- 150000004702 methyl esters Chemical class 0.000 claims description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 4
- 125000004001 thioalkyl group Chemical group 0.000 claims description 4
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 claims description 2
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 claims description 2
- BRNULMACUQOKMR-UHFFFAOYSA-N Thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 150000002829 nitrogen Chemical group 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 125000004429 atoms Chemical group 0.000 claims 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 1
- 229940113083 morpholine Drugs 0.000 claims 1
- 208000006673 Asthma Diseases 0.000 abstract description 4
- 230000001154 acute Effects 0.000 abstract description 4
- 230000000172 allergic Effects 0.000 abstract description 4
- 201000008937 atopic dermatitis Diseases 0.000 abstract description 4
- 230000035939 shock Effects 0.000 abstract description 4
- 206010061218 Inflammation Diseases 0.000 abstract description 3
- 210000004072 Lung Anatomy 0.000 abstract description 3
- 208000006641 Skin Disease Diseases 0.000 abstract description 3
- 230000001413 cellular Effects 0.000 abstract description 3
- 230000001605 fetal Effects 0.000 abstract description 3
- 230000002496 gastric Effects 0.000 abstract description 3
- 230000036039 immunity Effects 0.000 abstract description 3
- 230000004054 inflammatory process Effects 0.000 abstract description 3
- 230000035800 maturation Effects 0.000 abstract description 3
- 210000000056 organs Anatomy 0.000 abstract description 3
- 230000032696 parturition Effects 0.000 abstract description 3
- 230000036269 ulceration Effects 0.000 abstract description 3
- 208000004756 Respiratory Insufficiency Diseases 0.000 abstract description 2
- 201000004193 respiratory failure Diseases 0.000 abstract description 2
- 229920002678 cellulose Polymers 0.000 abstract 1
- 239000001913 cellulose Substances 0.000 abstract 1
- 230000004069 differentiation Effects 0.000 abstract 1
- 230000003389 potentiating Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 53
- 238000002360 preparation method Methods 0.000 description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- 239000011541 reaction mixture Substances 0.000 description 40
- 229910001868 water Inorganic materials 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- VKMGSWIFEHZQRS-NSHDSACASA-N (1R)-1-(3,4-dichlorophenyl)-2-(propan-2-ylamino)ethanol Chemical compound CC(C)NC[C@H](O)C1=CC=C(Cl)C(Cl)=C1 VKMGSWIFEHZQRS-NSHDSACASA-N 0.000 description 23
- 150000001412 amines Chemical class 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 14
- 238000004587 chromatography analysis Methods 0.000 description 13
- 239000006260 foam Substances 0.000 description 13
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- 239000003921 oil Substances 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 238000001914 filtration Methods 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 229940079593 drugs Drugs 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- RUYZRLREVCHREA-UHFFFAOYSA-N 6-(4-fluorophenyl)-1H-indole Chemical compound C1=CC(F)=CC=C1C1=CC=C(C=CN2)C2=C1 RUYZRLREVCHREA-UHFFFAOYSA-N 0.000 description 8
- NRPVKFYLFLYZEH-UHFFFAOYSA-N 6-(4-fluorophenyl)indole-1,3-dicarboxylic acid Chemical compound C=1C=C2C(C(=O)O)=CN(C(O)=O)C2=CC=1C1=CC=C(F)C=C1 NRPVKFYLFLYZEH-UHFFFAOYSA-N 0.000 description 8
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 125000005843 halogen group Chemical group 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 7
- 235000015450 Tilia cordata Nutrition 0.000 description 7
- 235000011941 Tilia x europaea Nutrition 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000004571 lime Substances 0.000 description 7
- 239000002502 liposome Substances 0.000 description 7
- HOQBAMABCMDWGP-UHFFFAOYSA-N 2-chloro-1-[6-(4-fluorophenyl)-1H-indol-3-yl]ethanone Chemical compound C1=CC(F)=CC=C1C1=CC=C(C(=CN2)C(=O)CCl)C2=C1 HOQBAMABCMDWGP-UHFFFAOYSA-N 0.000 description 6
- 210000001772 Blood Platelets Anatomy 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000004215 Carbon black (E152) Substances 0.000 description 5
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 235000020127 ayran Nutrition 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 150000002430 hydrocarbons Chemical class 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- WEAXQUBYRSEBJD-UHFFFAOYSA-N methyl 1H-indole-4-carboxylate Chemical compound COC(=O)C1=CC=CC2=C1C=CN2 WEAXQUBYRSEBJD-UHFFFAOYSA-N 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Inorganic materials [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 229940086542 triethylamine Drugs 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- ABOSMHRLVUWEMT-UHFFFAOYSA-N 4-ethoxy-3-nitropyridine Chemical compound CCOC1=CC=NC=C1[N+]([O-])=O ABOSMHRLVUWEMT-UHFFFAOYSA-N 0.000 description 4
- GTJSFEYOWIJQGE-UHFFFAOYSA-N Cl.C[N-]C Chemical compound Cl.C[N-]C GTJSFEYOWIJQGE-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- 125000002947 alkylene group Chemical group 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000003111 delayed Effects 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Inorganic materials [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ZXCIEWBDUAPBJF-MUUNZHRXSA-N 1-O-octadecyl-2-acetyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C ZXCIEWBDUAPBJF-MUUNZHRXSA-N 0.000 description 3
- KLDLRDSRCMJKGM-UHFFFAOYSA-N 3-[chloro-(2-oxo-1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one Chemical compound C1COC(=O)N1P(=O)(Cl)N1CCOC1=O KLDLRDSRCMJKGM-UHFFFAOYSA-N 0.000 description 3
- BHFUPJGHEWFFPE-UHFFFAOYSA-N 6-(4-fluorophenyl)-1H-indole-3-carbaldehyde Chemical compound C1=CC(F)=CC=C1C1=CC=C(C(C=O)=CN2)C2=C1 BHFUPJGHEWFFPE-UHFFFAOYSA-N 0.000 description 3
- VEAIRIZLNALHQP-UHFFFAOYSA-N 6-(4-fluorophenyl)-1H-indole-3-carboxylic acid Chemical compound C=1C=C2C(C(=O)O)=CNC2=CC=1C1=CC=C(F)C=C1 VEAIRIZLNALHQP-UHFFFAOYSA-N 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- PPSRARCZQBUQCB-UHFFFAOYSA-N benzyl N-[(4-carbonochloridoylcyclohexyl)methyl]carbamate Chemical compound C1CC(C(=O)Cl)CCC1CNC(=O)OCC1=CC=CC=C1 PPSRARCZQBUQCB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
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- 239000000969 carrier Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 3
- GQQQULCEHJQUJT-UHFFFAOYSA-N ethyl 4-aminopiperidine-1-carboxylate Chemical compound CCOC(=O)N1CCC(N)CC1 GQQQULCEHJQUJT-UHFFFAOYSA-N 0.000 description 3
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 3
- 150000003840 hydrochlorides Chemical class 0.000 description 3
- BXKWQVDDDMNJNV-UHFFFAOYSA-N indole-1,3,4-tricarboxylic acid Chemical compound C1=CC(C(O)=O)=C2C(C(=O)O)=CN(C(O)=O)C2=C1 BXKWQVDDDMNJNV-UHFFFAOYSA-N 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- VFQNWBVPKCQUKR-UHFFFAOYSA-N methyl 3-(2-chloroacetyl)-1H-indole-4-carboxylate Chemical compound COC(=O)C1=CC=CC2=C1C(C(=O)CCl)=CN2 VFQNWBVPKCQUKR-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000003000 nontoxic Effects 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 125000004430 oxygen atoms Chemical group O* 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 230000002335 preservative Effects 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 229910000080 stannane Inorganic materials 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 125000004862 thiobutyl group Chemical group 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
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- 239000003380 propellant Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 230000002685 pulmonary Effects 0.000 description 1
- ZZYXNRREDYWPLN-UHFFFAOYSA-N pyridine-2,3-diamine Chemical compound NC1=CC=CN=C1N ZZYXNRREDYWPLN-UHFFFAOYSA-N 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
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- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
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- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
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- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
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- 239000003206 sterilizing agent Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
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- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
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- 229940095064 tartrate Drugs 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000004014 thioethyl group Chemical group [H]SC([H])([H])C([H])([H])* 0.000 description 1
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 1
- 125000004035 thiopropyl group Chemical group [H]SC([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
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- 239000011778 trisodium citrate Substances 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-M undecanoate Chemical compound CCCCCCCCCCC([O-])=O ZDPHROOEEOARMN-UHFFFAOYSA-M 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical class CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 1
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- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Abstract
The present invention relates: provides compounds of Formula I, and pharmaceutically acceptable salts thereof, which are potent platelet activating factor antagonists, and are useful in the treatment of disorders related to platelet activating factor, including asthma, shock, respiratory insufficiency syndrome, acute inflammation, rejection of transplanted organ, gastrointestinal ulceration, allergic skin diseases, cellular immunity delay, parturition, maturation of fetal lung, and cellulose differentiation
Description
DERIVATIVES OF INDOL-3-CARBONYL AND INDOL 3-SULFONYL AS ANTAGONISTS OF THE PLATELET ACTIVATING FACTOR
Technical Field This invention relates to compounds having pharmacological activity, to compositions containing these compounds, and to a medical method of treatment employing the compounds and compositions. More particularly, this invention relates to certain indole-3-carbonyl and indole-3-sulphonic acid derivatives and their salts, which have an activating antagonist of platelet activating factor (PAF), to pharmaceutical compositions containing to these compounds, and to a method for the treatment of disorders mediated by platelet activating factor.
BACKGROUND OF THE INVENTION Platelet activating factor (PAF) is a phospholipid released from human cells and other animal cells, and is an acetylglyceryl ether of phosphorylcholine, as represented by the following formula:
CH20 (CH2) nCH3 CH ^ COO-CH OC IH20-PII-O (CH2) 2-N + (CH3) 3 s where n is 15 or 17. Platelet activating factor is physiologically active, and causes smooth muscle contraction of airways, increased vascular permeability, platelet accumulation, hypotension, and the like. It is now recognized as a powerful mediator of inflation, and may have a physiological or pathobiological role in a variety of clinical conditions, such as asthma and pulmonary dysfunction, acute inflation, transplant organ rejection, shock, thrombosis, anaphylaxis, gastrointestinal ulceration, allergic skin diseases, retinal and corneal diseases, chemically induced liver cirrhosis, and ovi-implantation in pregnancy. In accordance with the above, compounds that possess antagonistic effects of platelet activating factor, should be valuable in the treatment of any of the above conditions.
SUMMARY OF THE INVENTION The present invention provides in its main aspect, compounds having an antagonist activity of platelet activating factor of Formula I:
or a pharmaceutically acceptable salt thereof, wherein R1 is one or more groups independently selected from the group consisting of: (a) hydrogen, (b) halogen, (c) hydroxy, (d) cyano, (e) alkyl of one to six carbon atoms, (f) alkenyl of two to six carbon atoms, (g) alkynyl of two to six carbon atoms, (h) alkoxy of one to six carbon atoms, (i) alkanoyl of one to seven carbon atoms, (j) -COOR7, wherein R7 is hydrogen, alkyl of one to ten carbon atoms, or phenylalkyl, wherein the alkyl portion is one to four carbon atoms, (k) phenyl unsubstituted, (1) phenyl, substituted with alkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, halogen, -NR8R9, wherein R8 and R9 are independently selected from hydrogen and alkyl of one to six carbon atoms, or R8 and R9 together with the nitrogen atom to which they are attached, form a pyrrolidinyl ring, pip eridinyl, piperazinyl, or morpholinyl, -COOR7, -C (0) NR8R9, or -S02NR8R9, (m) -C (0) NR8R9, (n) -0C (0) NR8R9, (o) -NHC (0) NR8R9 , (p) 2- or 3-furyl, (q) 2- or 3-thienyl, (r), 2-, 4-, or 5-thiazolyl, (s) 2-, 3, or 4-pyridyl, ( t) 2-, or 4-pyrimidyl, (u) phenylalkyl, wherein the alkyl portion is from one to six carbon atoms, (v) phenylalkyl, wherein the alkyl portion is from one to six carbon atoms, and the phenyl moiety is substituted with halogen, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms, (w) unsubstituted benzoyl, (x) benzoyl substituted with halogen, alkyl of one to six carbon atoms, carbon, or alkoxy of one to six carbon atoms, (and) unsubstituted phenoxy, (z) phenoxy substituted by halogen, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms, (aa) unsubstituted phenylalkyloxy , wherein the alkyl portion is from one to six carbon atoms, (bb) phenylalkyloxy, wherein the alkyl portion is from one to six carbon atoms, and the phenyl moiety is substituted with halogen, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms, (ce) phenyl- unsubstituted alkanoyl, wherein the alkanoyl portion is from one to seven carbon atoms, and (dd) phenylalkanoyl, wherein the alkanoyl portion is from one to seven carbon atoms, and the phenyl moiety is substituted with halogen, alkyl from one to six carbon atoms, or alkoxy of one to six carbon atoms. R2 is selected from the group consisting of: (a) hydrogen, (b) alkyl of one to six carbon atoms; (c) - (CH2) pC00R7, where p is 0, 1, 2, 3 or 4, (d) - (CH2) qNR8R9, where q is 2, 3 or 4, (e) - (CH2) pC0R7 , (f) - (CH2) qOR7, (g) - (CH2) pS02R7, (h) - (CH2) pS02NR8R9, (i) - (CH2) pCONR10R11 wherein R10 and R11 are independently selected from the group consisting of in hydrogen, alkyl of one to six carbon atoms, - (CH2) rCOOR7, wherein r is 1, 2, 3, or 4, - (CH2) rNR8R9, - (CH2) r0H, - (CH2) rS02R7, and - (CH2) rS02NR8R9, or R10 and R11 taken together define a ring of pyrrolidine, orpholine, or thiomorpholine, (j) - (CH) pCN, (k) - (CH2) p-lH-tetrazol-5-yl, ( 1) -C0NHNH2, () unsubstituted phenylalkyl, wherein the alkyl portion is one to carbon atoms, and (n) phenylalkyl, wherein the alkyl portion is from one to four carbon atoms, and the phenyl moiety is substituted with halogen, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms. R3 is selected from hydrogen and alkyl of one to six carbon atoms, and is selected from the group consisting of > C = 0, and > S (0) t, where t is 1 or 2, and and Z are independently CH or N. R 4 is selected from the group consisting of: (a) alkyl of one to six carbon atoms, (b) alkenyl of two to six carbon atoms, (c) alkynyl of two to six carbon atoms, (d) alkoxy of one to six carbon atoms, (e) thioalkyl of one to six carbon atoms, (f) alkoxyalkyl, wherein the alkoxy and alkyl portions are independently from one to six carbon atoms, (g) alkylthioalkyl, wherein the alkyl portions are independently from one to six carbon atoms, (h) haloalkyl from one to six carbon atoms, ( i) unsubstituted phenylalkyl, wherein the alkyl portion is from one to six carbon atoms, (j) phenylalkyl, wherein the alkyl portion is from one to six carbon atoms, and the phenyl is substituted with alkyl of one to six carbon atoms, haloalkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, hydroxy or halogen, (k) cycloalkyl of three to eight carbon atoms, (1) unsubstituted thiophenyl, and (m) thiophenyl substituted with alkyl of one to six carbon atoms, haloalkyl of one to six carbon atoms, alkoxy of one to six carbon, hydroxy, or halogen atoms. R5 and R6 are independently selected from the group consisting of hydrogen, alkyl of one to six carbon atoms, halogen, haloalkyl and alkoxy of one to six carbon atoms, m is 0 or 1, and n is 0, 1 or 2 , in the understanding that when Z is nitrogen, n can not be zero or one. The compounds of the present invention may exhibit stereoisomerism, by virtue of the presence of one or more asymmetric or chiral centers in the compounds. The present invention contemplates the different stereoisomers and mixtures thereof. The desired enantiomers are obtained by chiral synthesis from commercially available chiral starting materials, by methods well known in the art, or they can be obtained from mixtures of the enantiomers by resolution or using known techniques. In another aspect, the present invention provides pharmaceutical compositions useful for the treatment of disorders mediated by platelet activating factor, which comprise a therapeutically effective amount of a compound of the Formula I above, in combination with a pharmaceutically acceptable carrier. In another aspect, the present invention provides a method for inhibiting the activity of platelet activating factor, by administering to a host mammal in need of such treatment, an effective amount of a platelet activating factor inhibiting compound having the sture I previous. In still another aspect of the present invention, there is provided a method for the treatment of disorders mediated by platelet activating factor, including asthma, shock, respiratory distress syndrome, acute inflammation, delayed cellular immunity, parturition, maturation of fetal lung, and cell differentiation, by administration to a host mammal in need of such treatment, of a therapeutically effective amount of a compound of sture I above.
Detailed Description of the Invention Definition of Terms As used throughout this specification and the appended claims, the following terms have the specified meanings. The term "alkyl" refers to a monovalent group derived from a straight or branched chain saturated hydrocarbon, by the removal of a single hydrogen atom. Alkyl groups are exemplified by methyl, ethyl, normal propyl and isopropyl, normal butyl, secondary butyl, isobutyl and tertiary butyl, and the like. The term "thioalkyl" refers to an alkyl group, as defined above, attached to the parent molecular moiety through a sulfur atom, and includes examples such as thiomethyl, thioethyl, thiopropyl, normal thiobutyl, secondary thiobutyl, and tertiary thiobutyl. , and similar. The term "alkylthioalkyl" refers to a thioalkyl group, as defined above, attached to the parent molecular moiety through an alkylene group, and includes examples such as methylthiomethyl, ethylthiomethyl, propylthio-methyl, normal butyl, secondary and tertiary- thiomethyl, and the like. The term "alkanoyl" represents an alkyl group, as defined above, attached to the parent molecular moiety through a carbonyl group. The alkanoyl groups are exemplified by formyl, acetyl, propionyl, butanoyl, and the like. The terms "alkoxy" or "alkoxy" denote an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. Representative alkoxy groups include methoxy, ethoxy, propoxy, butoxyl, and the like. The term "alkoxyalkyl" refers to an alkoxy group, as defined above, linked through an alkylene group with the parent molecular moiety. Representative alkoxyalkyl groups include methoxymethyl, ethoxyethyl, ethoxyethyl, and the like. The term "alkoxycarbonyl" represents an ester group; that is, an alkoxy group attached to the parent molecular moiety through a carbonyl group. Representative examples include ethoxycarbonyl, ethoxycarbonyl, and the like. The term "alkenyl" denotes a monovalent group derived from a hydrocarbon containing at least one carbon-carbon double bond, by the removal of a single hydrogen atom. Alkenyl groups include, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. The term "alkylene" denotes a bivalent group derived from a straight or branched chain saturated hydrocarbon, by the removal of two hydrogen atoms, for example, methylene, 1,2-ethylene, 1,1-ethylene, 1, 3-propylene, 2,2-dimethylpropylene, and the like. The term "alkenylene" denotes a bivalent group derived from a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond. Examples of alkenylene include -CH = CH-, -CH2CH = CH-, -C (CH3) = CH-, -CH2CH = CHCH2-, and the like. The term "alkynylene" refers to a bivalent group derived by the removal of two hydrogen atoms from a straight or branched chain acyclic hydrocarbon group containing a carbon-carbon triple bond. Examples of alkynylene include -CH = CH-, -CH = CH-CH2-, -CH = CH-CH (CH3) -, and the like. The term "cycloalkyl" denotes a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound, by the removal of a single hydrogen atom. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2. l] heptanil, and bicyclo [2.2.2] octanyl. The term "cycloalkylene" refers to a bivalent group derived from a saturated carbocyclic hydrocarbon, by the removal of two hydrogen atoms, for example, cyclopentylene, cyclohexylene, and the like. The term "haloalkyl" denotes an alkyl group, as defined above, having one, two or three halogen atoms attached thereto, and is exemplified by groups such as chloromethyl, bromoethyl, trifluoromethyl, and the like.
The term "phenoxy" refers to a phenyl group attached to the parent molecular moiety through an oxygen atom. The term "phenylalkyloxy" refers to a phenyl group attached to the parent molecular moiety through an alkylene group, and thence through an oxygen atom. Representative phenylalkyloxy groups include phenylmethoxy, phenylethyl-2-oxy, phenylprop-3-yloxy, phenylprop-2-yloxy, and the like. The term "phenylalkanoyl" as used herein, refers to a phenyl group attached to the parent molecular moiety through an alkyl group, and thence through a carbonyl group. The term "thiophenyl" refers to a phenyl group attached to the parent molecular moiety through a sulfur atom. "Pharmaceutically acceptable salt" means those salts which, within the scope of medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a proportion of reasonable benefit / risk. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. The salts can be prepared on site during the isolation and final purification of the compounds of the invention, or separately, by reaction of the free base function with a suitable organic acid. Representative acid addition salts include acetate, adipose, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorrate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, salts of valerate, and the like. Representative alkaline or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine , dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. The terms "disorders related to platelet-activating factor" and "disorders mediated by PAF" are used herein to mean disorders related to platelet activating factor or mediated by platelet-activating factor, including asthma, shock, syndromes of respiratory insufficiency, acute inflammation, gastric ulceration, rejection of transplanted organ, psoriasis, allergic skin disease, ischemia and repercussion injury, delayed cellular immunity, parturition, fetal lung maturation, and cell differentiation.
Preferred Modalities In a preferred embodiment, the compounds of this invention are represented by Formula I, wherein R 1 is one more groups independently selected from the group consisting of: (a) hydrogen, (b) halogen, (c) alkyl from one to six carbon atoms, (d) alkynyl of two to four carbon atoms, (e) alkoxy of one to six carbon atoms, (f) phenyl, optionally substituted with alkyl of one to six carbon atoms, alkoxy from one to six carbon atoms, or halogen, (f) -COOR7, wherein R7 is hydrogen, alkyl of one to ten carbon atom, or phenylalkyl, wherein the alkyl portion is one to four carbon atom, (g) -C (0) NR8R9, (h) -OC (0) NR8R9, (i) 2- or 3-furyl, and (j) 2- or 3-thienyl; R2 was previously defined; R3, R5 and R6 are hydrogen; And it's > C = 0 or > S (0) 2; and R 4 is alkyl of one to six carbon atoms. In a more preferred embodiment, the compounds of this invention are represented by Formula 1, wherein R2 is selected from the group consisting of: (a) -CONR10R1: L, wherein R10 and R11 are independently selected from hydrogen and alkyl of one to six carbon atoms, and (b) - (CH2) qOR7, wherein q is 2, 3 or 4, and R7 is alkyl of one to four carbon atoms; and Y, R1, R3, R4, R5 and R6 were defined immediately before. In a still more preferred embodiment, the compounds of this invention are represented by Formula I, wherein W is N, and Y, R1, R2, R3, R4, R5 and R6 were defined immediately above. In the most preferred embodiment, the compounds of this invention are represented by Formula I, wherein it is CH or N, Z is CH; m is 0 or 1; n is 0 or 1, with the understanding that m and n are not both 0 or 1; and Y, R1, R2, R3, R4, R5 and R6 were defined immediately before. Compounds that are contemplated to fall within the scope of the present invention include, but are not limited to: dimethyl amide of 6- (4-fluorophenyl) -3- acid. { [4- (lH-2-methylimidazo [4.5-c] pyrid-1-yl) piperidin-1-yl] carbonyl} indole-1-carboxylic acid, 6- (4-fluorophenyl) -3-. { [4- (1H-2-methylimidazo [4.5-c] pi id-1-yl) piperidin-1-yl] carbonyl} indole, 3-. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) piperidin-1-yl] carbonyl} indole, 4-methyl ester of 1-dimethyl amide of 3- acid. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) piperidin-1-yl] carbonyl} indole-1, 4-dicarboxylic acid, 4-methyl ester of amide 1-dimethyl of acid 3-. { [4- (lH-2-methylimidazo [4.5-c] pyrid-1-yl) methylpiperidin-1-yl] carbonyl} indole, 4-dicarboxylic, dimethyl amide of 6- (4-fluorophenyl) -3- acid. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) methylpiperidin-1-yl] carbonyl} indole-1-carboxylic acid, dimethyl amide of 4-chloro-3- acid. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) methylpiperidin-1-yl] carbonyl} indole-l-carboxyl ico, l- (2-ethoxyethyl) -6- (4-f luorofenyl) -3-. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) methylpiperidin-1-yl] carbonyl} indole, 1- (2-ethoxyethyl) -4-chloro-3-. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) methylpiperidin-1-yl] carbonyl} indole, 4-methyl ester of 1-dimethyl amide of 3- [-] acid. { 4- [2- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) ethyl] piperazin-1-yl} carbonyl] indole-1, 4-dicarboxylic acid, dimethyl amide of 6- (4-f luorofenyl) -3- [. { 4- [2- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) ethyl] piperazin-1-yl} carbonyl] indole-1,4-dicarboxylic acid, tertiary butyl ester of 6- (4-fluorophenyl) -3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] sulfonyl} indole-1-carboxylic acid, 6- (4-fluorophenyl) -3-. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] sulfonyl} indole, dimethyl amide of 6- (4-fluorophenyl) -3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] sulfonyl} indole-1-carboxylic acid, tertiary butyl ester of 6- (4-fluorophenyl) -3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) methylpiperidin-1-yl] sulfonyl} indole-1-carboxylic acid, 6- (4-fluorophenyl) -3-. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) methylpiperidin-1-yl] sulfonyl} indole, dimethyl amide of 6- (4-fluorophenyl) -3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) methylpiperidin-1-yl] sulfonyl} indole-1-carboxylic acid, dimethyl amide of 6- (4-fluorophenyl) -3- [. { 4-2- (1 H-2-methylimidazo- [4,5-c] pyrid-1-yl) ethyl] piperazin-1-yl} sulfonyl] indole-1-carboxylic acid, 6- (4-fluorophenyl) -3-. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole, dimethyl amide of 6- (4-fluorophenyl) -3- acid. { [4- (1 H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole-l-carboxylic acid, methyl ester of 3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole-4-carboxylic acid, 4-methyl-amide-1-dimethyl ester of 3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole-1, 4-dicarboxylic acid, l- (2-ethoxyethyl) -3- methyl ester. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole-l-carboxylic, 4-chloro-3-. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole, 1- (2-ethoxyethyl) -4-chloro-3-. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole, dimethyl amide of 4-chloro-3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole-l-carboxylic acid, 4 -met i 1-3 -. { [4- (1H-2-methylimidazo- [4.5-c] p ir id-1-yl) piperidin-1-yl] acetyl} indole, 1- (2-ethoxyethyl) -4-methyl-3-. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole, dimethyl amide of 4-methyl-3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole-1-carboxylic acid, 3-dimethyl amide of 3-acid. { [trans -4- [(1H-2-methylimidazo- [4,5-c] pyrid-1-yl) methylcyclohex-1-yl] carbonyl} indole-1, 4-dicarboxylic acid, 4- (fur-2-yl) -3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) methylpiperidin-yl] carbonyl} indole-l-carboxylic acid, 4- (thien-2-yl) -3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) methylpiperidin-yl] carbonyl} indole-l-carboxylic acid, 4-ethynyl-3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) methylpiperidin-yl] carbonyl} indole-1-carboyl, dimethyl amide of 4-methoxy-3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) methylpiperidin-yl] carbonyl} -indole-1-carboxylic acid, dimethyl amide of 4- (N, N-dimethylamino-carbonyloxy) -3-. { [4- (1 H-2-methylimidazo- [4,5-c] pyrid-1-yl) ethylpiperidin-yl] carbonyl} -indol-l-carboxylic acid, and dimethyl amide of 4- (N, N-dimethylaminocar-boni lamino) -3- acid. { [4- (1 H-2-methylimidazo- [4,5-c] pyrid-1-yl) ethylpiperidin-yl] carbonyl} -indol-l-carboxylic acid.
Inhibitory Activity of Platelet Activating Factor of the Compounds of the Present Invention The ability of the representative compounds of the present invention to inhibit the activity of platelet activating factor in an in vitro test was determined using the following method. Citrated whole rabbit blood was obtained from Pel-Freez (Rogers, AR). Rabbit platelets were prepared by centrifugation and washing. The platelets were used by freeze-thawing and sonification; platelet membranes were prepared by centrifugation and washing. The final frozen membrane preparations were stored in 10 mM Tris / 5 mM MgCl2 / 2 mM EDTA (TME regulator, pH 7.0), adding 0.25 M sucrose for membrane stabilization. The standard platelet activating factor receptor binding assay contained 10 micrograms of platelet membrane protein, 0.6 nM [3H] C18-PAF (from Amersham or New England Nuclear, specific activity of 120-180 Ci / millimole), with and without test compound, in a "binding regulator" consisting of TME with zero bovine albumen at 0.25 percent aggregate (Sigma, RIA grade). The final assay volume was 100 microliters. The assay was conducted on Millititre-GVMR filter plates (Millipore Corp.); the incubation time was for 60 minutes at room temperature (22-23 ° C). The "specific binding" was operationally defined as the arithmetic difference between the "total link" of 0.6 nM [3H] C18-PAF (in the absence of added platelet activating factor),. and "non-specific binding" (in the presence of 1 μM PAF). After the prescribed incubation, the platelet membranes were filtered under vacuum and washed with one milliliter of "binding buffer". The filters were dried and removed. The bound radioactivity was quantified with a Berthold TLC Linear Analyzer model LB2842. Response curves were conducted at the dose of inhibition of the specific binding of [3H] C18-PAF by the test compounds, in triplicate, with at least four doses covering the active range. The experiments were repeated at least once. The IC50 values (concentration that produces a 50 percent inhibition) were determined by point-to-point evaluation. The K¿ values of the inhibition binding constants were calculated according to the method of Cheng and Prusoff [Bioche. Pharmacol. 22 (1973) 3099-3108], wherein:
? ] £ s x ~ 1 + ([[3H] PAF] / K < j [3H] PAF
IC50 1 + (0.6 n.M / 0.6 nM)
IC50
The K¿ values for the representative compounds of the present invention appear in the Table
1.
Table 1
? i (nM) ° Example KL (nM) or Example% inhibition of inhibition
1 3.3 16 250 2 44 17 1.2 3 100 18 110 4 140 19 95 5 74 20 2.5 6 2.5 21 14 7 18 22 12 8 1.2 23 5.2 9 29 24 30 10 200 25 10 11 30 26 12 12 340 27 71 13 32 % @ 1.0 M 28 0.5 14 120 29 2.0 15 65 30 2.4
Pharmaceutical Compositions The present invention also provides pharmaceutical compositions comprising one or more of the compounds of Formula I formulated above, together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions can be formulated especially for oral administration in solid or liquid form, for parenteral injection, or for rectal administration. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, locally (or by powders, ointments or drops), buccally, or as an oral or nasal spray. The term "parenteral" administration, as used herein, refers to modes of administration that include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, and intraatrial injection and infusion. The pharmaceutical compositions of this invention for parenteral injection comprise solutionssterile, pharmaceutically acceptable aqueous or non-aqueous dispersions, suspensions or emulsions, as well as sterile powders for reconstitution in sterile injectable solutions or dispersions just before use. Examples of carriers, diluents, solvents, or aqueous and non-aqueous vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as as olive oil), and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain auxiliaries, such as preservatives, wetting agents, emulsifying agents and dispersing agents. The prevention of the action of microorganisms can be ensured by the inclusion of different antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be done by using a liquid suspension of crystalline or amorphous material with poor solubility in water. The rate of absorption of the drug then depends on its rate of dissolution, which in turn, may depend on the size of the crystal and the crystalline form. In an alternative manner, delayed absorption of a parenterally administered drug is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the drug in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of the drug to the polymer, and the nature of the particular polymer employed, the rate of release of the drug can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by trapping the drug in liposomes or in microemulsions that are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacteria retention filter, or by the incorporation of sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or in another Sterile injectable medium just before use. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or calcium diphosphate and / or (a) fillers or extenders, such as starches, lactose, sucrose , glucose, mannitol and silicic acid, (b) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia, (c) humectants, such as glycerol, (d) disintegrating agents, such as agar agar, calcium carbonate, potato starch or tapioca, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents, such as paraffin, (f) absorption accelerators, such as quaternary ammonium compounds, (g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents, such as kaolin and bentonite clay, and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise pH regulating agents. Solid compositions of a similar type can also be employed as fillers in soft and hard gelatin capsules using excipients, such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. Optionally they may contain opacifying agents, and may also be of a composition that they release the active ingredients only, or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of the embedment compositions that can be used include polymeric substances and waxes. The active compounds may also be in a microencapsulated form, if appropriate, with one or more of the aforementioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate. , ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, peanut, corn, germ, olive oil, of castor bean and sesame seeds), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof. In addition to the inert diluents, the oral compositions may also include auxiliaries, such as wetting agents, emulsifying and suspending agents, sweeteners, flavors, and perfuming agents. The suspensions, in addition to the active compounds, may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose-lina, aluminum metahydroxide, bentonia, agar-agar and tragacanth, and mixtures thereof. thereof. Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of this invention with non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, or a suppository wax which are solids at room temperature, but liquid at body temperature, and therefore, that melt in the rectum or vaginal cavity, and that release the active compound. The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form may contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are phospholipids and phosphatidyl-cholines (lecithins), both natural and synthetic. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology. Volume XIV, Academic Press, New York, N.Y. (1976), pages 33 et seq. Dosage forms for local administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, pH regulators, or propellants that may be required. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as within the scope of this invention. The actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied to obtain an amount of the active compounds that is effective to achieve the desired therapeutic response for a particular patient, the compositions and the mode of administration. The selected dosage level will depend on the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the ability of the technique to initiate the doses of the compound at levels lower than those required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. In general, dosage levels of from about 0.001 to about 100 milligrams, more preferably from about 0.01 to about 20 milligrams, and most preferably from about 0.1 to about 10 milligrams of active compound per kilogram of body weight are orally administered to a mammalian patient. body. If desired, the effective daily dose can be divided into multiple doses for administration purposes, for example, from two to four separate doses per day.
Preparation of the Compounds of the Invention The compounds of this invention can be prepared by a variety of synthetic routes. The representative procedures are illustrated below. It should be understood that the groups R1, R2, R3, R4, R5, R6 and Z correspond to the groups identified above. The preparation of the compounds wherein Y is CO, and is N, is illustrated in Scheme 1. The coupling of standard indole-3-carboxylic acid peptides 1, for example, using bis (2-oxo-3-oxazolidinyl) chloride ) phosphinic (BOP-Cl) and amine 2, gives the compounds where m = 0. The compounds of the invention wherein m = 1 are prepared by the reaction of chloroacetylindole 4 with amine 2 in a polar solvent, such as N, N-dimethyl formamide in the presence of a base, for example, N, N-diisopropylethyl amine, followed by the introduction of the group R2 using a base, such as NaH or KOH and R2X, wherein X is a suitable leaving group, such as Cl, Br, I, methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl.
Scheme I
The preparation of the compounds wherein Y is S02, and is N, is shown in Scheme 2. Bromoindole 6 is converted to chlorosulfonylindole 7 by metalation using, for example, t-BuLi, followed by the reaction with S02 gas and N-chlorosuccinimide. The displacement of Cl with amine 2 in the presence of a base, such as triethyl amine, gives 8. The removal of the tertiary-carbonyl butoxy group, for example, using sodium methoxide, gives 9, which becomes the desired compound by its reaction with a base and R2X as described above.
Scheme 2
NaO e
The compounds of the invention wherein W and Z are both CH, are prepared as described in Scheme 3. The reaction of indole 11 with ethyl magnesium bromide, ZnCl2, and 12-chloride gives 3-acylindole. . The group R2 is then introduced by the reaction of .13 with a base and R2X as described above, to give the 14. The removal of the benzyloxycarbonyl group with H2 catalysed by palladium on carbon, followed by condensation of the primary amine with 3-nitro-4-ethoxypyridine, gives 16. Reduction of the nitro group using, for example, SnCl 2, gives diamine 12, which is converted to the desired compound 1.8 by reaction, for example, with (R 4 CO) and RC02H, wherein R4 is alkyl or haloalkyl; R4C0C1, wherein R4 is aryl; or ethyl cycloacetate (ethoxymethylene), wherein R 4 is H.
Scheme 3
Preparation of Amine Intermediates The preparation of the amines 2 used above is illustrated in Scheme 4. The primary amine 19, wherein P is H or optionally a suitable protecting group, such as acetyl or ethoxycarbonyl, is condensed with 3-nitro -4-ethoxypyridine to give 2_0. Reduction of the nitro group, for example, by palladium-on-carbon hydrogenolysis, gives diamine 2_1, which is then converted to 22., for example, with (R4C0) 20 and R4C02H, wherein R4 is alkyl or haloalkyl; R4C0C1, wherein R4 is aryl; or ethyl (ethoxymethylene) cyanoacetate, wherein R4 is H. Deprotection of 22 using an aqueous base, such as KOH or LiOH in alcohol, yields 2. The preparation of the representative amines is illustrated below.
Scheme 4
Amina lH-l (piperidin-4-yl) -2-methylf 4.5-c 1 imidazopyridine
Step 1; 3-Nitro-4-fN- (l-ethoxycarbonylpiperidin-4-yl) aminopyridine. A mixture of ethyl 4-amino-1-piperidinecarboxylate (3.53 grams, 20.5 milliliters) and 4-ethoxy-3-nitropyridine (3.65 grams, 21.7 millimoles) in CH 3 CN (25 milliliters) was heated to reflux for 40 hours. The reaction mixture was cooled to room temperature, and concentrated in vacuo to give an orange syrup, which was used without further purification.
Step 2; 3, 4- f N- (l-ethoxycarbonylpiperidin-4- iDdiaminopyridine) Catalytic hydrogenation (10 percent Pd / C, 1 atmosphere H2, ethanol) of 3-nitro-4 [N- (1-ethoxycar- bonilpiperidin-4-yl)] aminopiperidin-4-yl)] aminopyridine prepared in Step 1, gave 6.22 grams of 3, 4- [Nl-ethoxycarbonylpiperidin-4-yl]] diaminopyridine, which was used without further purification .
Step 3; lH-l- (l-ethoxycarbonylpiperidin-4-yl) -2-methyl r4.5-c] imidazopyridine. A solution of 3, 4- [N- (1-ethoxycarbonylpiperidin-4-yl) diaminopyridine (6.22 grams) prepared in Step 2, in acetic anhydride (50 milliliters), was heated to reflux for 70 hours. The reaction mixture was cooled to room temperature, and the acetic anhydride was quenched by the slow addition of methanol. The reaction mixture was concentrated in vacuo, and the residue was partitioned between CH2C12 and saturated aqueous Na2CO3. The organic phase was concentrated in vacuo. Chromatography on silica gel (1 triethyl amine: 3 methanol: 96 CH2C12 gave 1H-1- (1-ethoxycarbonylpiperidin-4-yl) -2-methyl [4,5-c] imidazopyridine (3.7 grams).
Step 4: 1H-1- (piperidin-4-yl) -2-methyl [4,5-c] imidazopyridine, To a solution in 95 percent ethanol (20 milliliters) of 1H-1- (l-ethoxycarbonylpiperidin-4-) il) -2-methyl [4,5-c] imidazopyridine (3.7 grams, 12.8 mmol), prepared in Step 3, was added a solution of powdered KOH (2.47 grams, 44 mmol) in H20 (8 milliliters). The reaction mixture was heated to reflux for 72 hours. The reaction mixture was cooled to room temperature, and diluted with H20 (50 milliliters). The solution was continuously extracted in CH2C12 for 7 hours. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give lH-1 - (piperidin-4-yl) -2-methyl [4,5-c] imidazopyridine (2.07 grams) as a yellow solid.
Amina 2 1H-1- (piperidin-4-ylmethyl) -2-methyl T4.5-cl imidazopyridine
Step 1: 1H-1- (piperidin-4-ylmethyl) -2-methyl r 4.5-cl imidazopyridine. The desired compound (3.71 grams) was prepared according to the method of Amin 1, Steps 1-3, except that 4-aminomethylpiperidine was used to replace ethyl 4-amino-1-piperidinecarboxylate.
Step 2; lH-1 - (Pperidin-4-ylmethyl) -2-methyl-3,4-c] imidazopyridine. To a solution in absolute ethanol (40 milliliters) of 1H-1- (acetylpiperidin-4-ylmethyl) -2-methyl [4,5-c] imidazopyridine (3.7 grams, 13.6 millimoles), prepared in Step 1, was added a LiOH solution «H20 in H20 (15 milliliters). The reaction mixture was refluxed for 20 hours, then diluted with brine (100 milliliters), and extracted continuously in CH2Cl2 for 20 hours. The organic phase was dried over MgSO, filtered and concentrated in vacuo to give 1H-1- (piperidin-4-ylmethyl) -2-methyl [4,5-c] imidazopyridine (2.51 grams) as a yellow foam.
Amin 3 lH-l-f2- (piperazin-1-yl) ethyl-2-methyl C4.5-c1 imidazopyridine The desired compound was prepared according to the method of Amina 1, with the exception that l- ( 2-aminoethyl) piperazine to replace ethyl 4-amino-1-piperidinecarboxylate.
Preparation of Intermediates of indole Indole l l-dimethyl amide of 6- (4-fluorophenyl) indole-1,3-dicarboxylic acid
Step 1; 6- (4-fluorophenyl) indole-3-carboxaldehyde To a solution of dimethyl formamide (5.0 milliliters, 64 mmol) and CH2C12 (120 milliliters), oxalyl chloride (2.1 milliliters, 24 mmol) was added. The mixture was stirred for 45 minutes at room temperature, and then decanted into a solution of 6- (4-fluorophenyl) indole.
(5.1 grams, 24 millimoles), which was prepared as described in International Application Number PCT / USA92 / 05890 (February 4, 1993). The reaction mixture was stirred for 90 minutes at room temperature, and the iminium salt was isolated by filtration. The solids were dissolved in methanol (150 milliliters), and saturated aqueous NaHCO3 (200 milliliters) was added. The resulting precipitate was filtered and dried in a vacuum oven, to give 6- (4-fluorophenyl) indole-3-carboxaldehyde (4.14 grams, 72 percent) as a tan powder.
Step 2; Dimethyl amide of 6- (4-fluorophenyl) indole-3-carboxaldehyde-1-carboxylic acid. To a solution in tetrahydrofuran (175 milliliters) of 6- (4-fluorophenyl) indole-3-carboxaldehyde (4.14 grams, 17.3 millimoles), prepared in Step 1, was added KOH powder (5.10 grams)., 91 millimoles). After stirring for 3 minutes, N, N-dimethylcarbamyl chloride (1.8 milliliters, 20 mmol) was added and stirring was continued for 90 minutes. The reaction mixture was diluted with ethyl acetate (1 liter), and washed with a regulator with a pH of 7. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give 5.22 grams of a solid. which contained approximately 8 percent of the starting material. The above procedure was then repeated to give dimethyl amide of 6- (4-fluorophenyl) indole-3-carboxaldehyde-l-carboxylic acid (4.86 grams, 91 percent) as a tan solid.
Step 3: 1-dimethyl amide of 6- (4-fluorophenyl) indole-1,3-dicarboxylic acid. To a solution in tetrahydrofuran (25 milliliters) and tertiary butyl alcohol (70 milliliters) of dimethyl amide of 6- (4-fluorophenyl) indole-3-carboxaldehyde-1-carboxylic acid (437 milligrams, 1.4 mmol), prepared as in Step 2, 2-methyl-2-butene (2.0 M in tetrahydrofuran, 8.0 milliliters, 16 mmol) was added. A solution in H20 (20 milliliters) of NaC102 (1.2 grams, 13 mmol) and NaH2P04 (2.4 grams, 17 mmol) was added dropwise, and the reaction mixture was stirred overnight at room temperature. The solvents were removed in vacuo, and H20 (100 milliliters) was added to the residue. The pH was adjusted to 3 with concentrated HCl, the H0 was decanted, and the residue was taken up in ethyl acetate. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give a dark brown oil (0.53 grams). The oil was recovered in tetrahydrofuran and treated with activated charcoal. Filtration and removal of the tetrahydrofuran in vacuo gave 1-dimethyl amide of 6- (4-fluorophenyl) indole-1,3-dicarboxylic acid (0.43 grams, 93 percent) as a red solid.
Indole 2 6- (4-fluorophenyl) indole-3-carboxylic acid The desired indole was prepared according to the method of Indole 1, Steps 1 and 3. ndol 3 Ester 4-methyl amide 1-dimethyl indole acid 1, 3,4-tricarboxylic The desired indole was prepared according to the method of Indole 1, except that indole-4-carboxylic acid methyl ester was used to replace 6- (4-fluorophenyl) indole.
Indole 4-dimethyl amide of 4-chloroindol-1,3-dicarboxylic acid The desired indole was prepared according to the method of Indole 1, except that 4-chloroindole was used to replace 6- (4-fluorophenyl) indole.
Indole 5 6- (4-fluorophenyl) indole-3-sulfonyl chloride Step 1: Tertiary butyl ester of 6- (4-fluorofonyl) indole-1-carboxylic acid. The desired compound was prepared by treatment in a CH3CN solution of 6- (4-fluorophenyl) indole, with tertiary dibutyl dicarbonate and 4-dimethylaminopyridine.
Step 2; Tertiary butyl ester of 6- (4-fluorophenyl) -3-bromoindol-1-carboxylic acid. To a solution under N2 of tertiary butyl ester of 6- (4-fluorophenyl) indole-l-carboxylic acid (2.00 grams,
6. 42 mmol), prepared as in Step 1, in tetrahydrofuran (36 milliliters), N-bromosuccinimide (1.26 grams, 7.08 mmol) was added in a single portion, and the light orange solution was stirred overnight at room temperature. room temperature. The reaction mixture was diluted with ether (500 milliliters), and extracted with aqueous NaHS03 (1-2 M, 250 milliliters) and saturated aqueous NaHCO3. The organic phase was dried over Na 2 SO 4, filtered, and concentrated in vacuo to give a light yellow viscous oil (2.58 grams), which solidified upon standing.
Step 3; Tertiary l-butoxy-carbonyl-6- (4-fluorophenyl) indole-3-sulfonyl chloride. To a solution at -70 ° C under N2 of tertiary butyl ester of 6- (4-fluorophenyl) -3-bromoindol-1-carboxylic acid (1.00 grams, 2.56 mmol), prepared as in Step 2, in tetrahydrofuran (6 milliliters), tertiary butyl lithium (1.7 M in pentane, 3.00 milliliters, 5.10 mmol) was added. The reaction mixture was stirred for 15 minutes, and then S02 gas was bubbled into the solution for 5 to 10 minutes. The light orange solution was stirred for 2.5 hours at -60 ° C to -70 ° C, and then warmed to 0 ° C for 4 hours, during which time the excess S02 was distilled. Then hexane (20 milliliters) was added, which resulted in the formation of a heavy light brown oil. The hexane was decanted and replaced with CH2C12 (5 milliliters). The resulting light orange solution was cooled in an ice bath, and N-chlorosuccinimide (0.53 grams, 4.0 mmol) was added. The cold bath was removed, and the slurry was stirred for 75 minutes. The reaction mixture was diluted with CH2C12, and stirred with NaHS03, aqueous (1-2M, 50 milliliters). The resulting emulsion was separated with brine, and again the organic phase was stirred with aqueous NaHS03, then extracted with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a tan foam (1.13 grams). Chromatography on silica gel (20: 1, then 10: 1 hexane-ethyl acetate) gave tertiary-1-butoxy-carbonyl-6- (4-fluorophenyl) indole-3-sulfonyl chloride as a pale yellow oil. The azeotropy with CHC12 gave opaque yellow rosettes.
Indole 6 6- (4-fluorophenyl) -3-chloroacetylindole To a solution under N2 of 6- (4-fluorophenyl) indole
(10.0 grams, 47.4 millimoles) in dioxane (36 milliliters), pyridine (5.80 milliliters, 71.8 millimoles) was added, and the solution was heated to 60 ° C. A solution of chloroacetyl chloride (5.66 milliliters, 71.1 millimoles) in dioxane (12.5 milliliters) was added for one hour. The reaction mixture was stirred for one hour at 60 ° C, then cooled to room temperature, and partitioned between H20 and ether. The resulting orange precipitate was filtered, recrystallized from ethanol, and rinsed with cold ether, to give 6- (4-fluorophenyl) -3-chloroacetylindole (2.78 grams, 20 percent) fluorophenyl) -3-chloroacetylindole (2.78 grams, 20 percent) as an orange solid.
Indole 7 3-Chloroacetylindole-4-carboxylic acid methyl ester To a low N 2 solution of 4-methoxycarbonylindole (9.00 grams, 51.4 mmol) in anhydrous CH 2 C 12 (800 milliliters), ethylmagnesium chloride (3.0 M in ether, 17.2%) was added. milliliters, 51.6 millimoles) for 10 minutes. The reaction mixture was stirred for 20 minutes, and ZnCl2 (1.0 M in ether, 154 milliliters, 154 mmol) was added all at once, and stirring was continued for 20 minutes. A solution of chloroacetyl chloride (4.50 milliliters, 56.5 mmol) in CH2C12 (200 milliliters) was added over 15 minutes, and the reaction mixture was stirred for 70 hours at room temperature. The reaction mixture was poured into saturated aqueous NHC1, and the aqueous phase was extracted with CH2C12. The combined organic layers were washed with brine, dried over Na 2 SO 4, filtered, and concentrated in vacuo to give a viscous dark brown oil (13.6 grams). Chromatography on silica gel (1: 1, and then 2: 1 ethyl acetate-hexane) gave 3-chloroacetylindole-4-carboxylic acid methyl ester (6.60 grams, 51 percent) as yellow flakes.
Indole 8 4-chloro-3-chloroacetylindole The desired compound was prepared according to the method of Indole 7, with the exception that 4-chloroindole was used to replace the 4-methoxycarbonylindole.
Indole 9 4-methyl-3-chloroacetylindole The desired compound was prepared according to the method of Indole 7, with the exception that 4-methylindole was used to replace 4-methoxycarbonylindole.
Indole 10 Dimethyl amide of 4-bromoindol-l, 3-dicarboxylic acid The desired indole is prepared according to the method of Indole 1, with the exception that 4-bromoindole is used to replace 6- (4-fluorophenyl) indole . Indole II Dimethyl amide of 4-methoxyindole-l, 3-dicarboxylic acid The desired indole is prepared according to the method of Indole 1, with the exception that 4-methoxyindole is used to replace 6- (4- (fluorophenyl)) Indole The above can be better understood by the following Examples, which are presented for illustration and are not intended to limit the scope of the invention.
Example 1 Preparation of 6- (4-fluorophenyl) -3-lf4- (lH-2-methylimidazor4.5-c1pyrid-1-yl) piperidin-1-yl] carbonyl dimethyl amide hydrochloride} indole-1-carboxylic acid To a solution in tetrahydrofuran (6 milliliters) of dimethyl amide of 6- (4-fluorophenyl) indole-1,3-dicarboxylic acid (Indole 1) (0.106 grams, 0.33 millimole) N-amine was added, N-diisopropylethyl (0.1 milliliter, 0.57 millimole) and bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-Cl) (0.096 grams, 0.38 millimole). After 5 minutes, a solution in tetrahydrofuran (3 milliliters) of 1 H -l- (piperidin-4-yl) -2-methyl [4,5-c] imidazopyridine (Amin 1) (0.100 grams, 0.46 mmol) was added, and the reaction mixture was stirred for 20 hours at room temperature. The reaction mixture was partitioned between CH2C12 and saturated aqueous NaHCO3. The organic phase was dried over MgSO 4, filtered, and concentrated in vacuo to give 6- (4-fluorophenyl) -3- dimethyl amide. { [4-lH-2-methylimidazo [4.5-c] pyrid-1-yl) piperidin-1-yl] carbonyl} indole-l-carboxylic acid (0.146 grams) as a tan foam. The hydrochloride salt was prepared by treating a solution in ethyl acetate of the free base with a solution of 4 N HCl / dioxane, followed by filtration, m.p. 193-195 ° C.
X H NMR (CDCl 3, 300 MHz) d 9.02 (s, 1 H), 8.38 (d, 1 H, J = 6 Hz). 7.80 (s, 1H), 7.78 (d, 1H, J = 6 Hz), 7.60 (m, 3H), 7.52 (m, 1H), 739 (m, 1H), 7.16 (m, 2H), 4.52 (, 1H), 3.20 (m, 2H), 3.16 (s, 6H), 2.71 (s, 3H), 2.46 (m, 2H), 2.03 (m, 2H), 1.50 (m, 2H). IR (microscope) 3400 (br), 3080.2940, 1690, 1615, 1480, 1440, 1390 cm-1. MS (DCI / NH3) m / e 525 (M + H) ^. ? nd 'al | wra C30H29FN6O2 - HCl • 3 H20: C, 58.58; H, 5.90; N, 13.66. ,; ™. : C, 58.58; H, 5.72; N, 12.99.
Example 2 Preparation of 6- (4-fluorophenyl) -3- hydrochloride. { [4- (lH-2-methylimidazor-4-cl-irid-1-yl) piperidin-1-yl-1-carbonyl} Indole The desired compound was prepared according to the method of Example 1, with the exception that 6- (4-fluorophenyl) indole-3-carboxylic acid (Indole 2) was used to replace the N, N-dimethylcarbamoyl- 6- (fluorophenyl) indole-3-carboxylic acid. p.f. 120-123 ° C. X H NMR (DMSO-d 6, 300 MHz) d 9.01 (s, 1 H), 8.48 (d, 1 H, J = 6 Hz), 7.81 (d, 1 H, J = 8 Hz), 7.70 (d, 1 H, J = 3 Hz), 7.58 (m, 3H), 7.47 (m, 1H), 7.41 (m, 1H), 7.14 (ra, 2H), 4.48 (m, 1H), 3.62 (m, 2H), 3.19 (m, 1H), 2.71 (s, 2H), 2.48 (m, 2H), 2.03 (m, 2H). IR (microscope) 3100 (br), 2980, 2920, 1755, 1605, 1515, 1435 cm-1. MS (DCI / NH3) m / e 454 (M + H) +, 200.302, 130. Anal. lime. for C27H24FN50- 3 H20: C, 63.89; H, 5.96; N, 13.80 Encone. : C, 64.18; H, 6.08; Nv 12.67.
Example 3 Preparation of 3- hydrochloride. { r4- (lH-2-methylimidazo- 4.5-c1 pyrid-1-yl) piperidin-1-ip carbonyl indole The desired compound was prepared according to the method of Example 1, with the exception that indole acid was used -3-carboxylic acid to replace 1-N, N-dimethylcarbamoyl-6- (4-fluorophenyl) indole-3-carboxylic acid. p.f.
157-160 ° C. H NMR (DMSO-d6, 300 MHz) d 11.64 (bds, 1H), 9.39 (s, 1H), 8.58 (d, 1H, J = 8 Hz), 8.42 (d.IH, J = 8 Hz), 7.80 (d, 1H, J = 3 Hz), 7.78 (d, 1H, J = 7 Hz), 7.48 (d, 1H, J = 7 Hz), 7.16
(m, 2H), 4.88 (m, 1H), 4.54 (m, 2H), 3.21 (m, 2H), 2.84 (s, 3H), 2.32 (m, 2H), 2.09 (, 2H). GO . microscope) 3350 (br), 3 120 (br), 2620 (br), 1755. 1605, 1525 cm-1. MS (DCI / NH3) m / e 360 (M + H) +, 130. Al at cal For C21H21N5O • 2 HCl 1.5 H20: C, 54.91; H, 5.70; N, 15.25. e M C, 55.12; H, 5.65; N, 14.45.
Example 4 Preparation of amide-4-methyl ester dichloride of 3-f r4- (lH-2-methylimidazo-4,5-c1pyrid-1-yl) piperidin-1-yl acid} carbonyl} indolyl, 4-dicarboxylic The desired compound was prepared according to the method of Example 1, with the exception that 4-methyl amide-1-dimethyl ester of indole 1,3,4-tricarboxylic acid (Indole 3 ) to replace the 1- (dimethyl) amide of 6- (4-fluorophenyl) indole-1,3-dicarboxylic acid. p.f. 190-193 ° C (decomposition).
X H NMR (DMSO-δ 6, 300 MHz) d 9.39 (s, 1 H), 8.64 (d, ΔH J - 6 Hz), 8.58 (d, 1H, J = 6 Hz), 8.07 (s, IH), 7.90 (dd, 1H, J = 0.5, 7 Hz), 7.71 (d ?, 1H, J = 0.5, 7 Hz), 7.43 (t, 1H, J = 6 Hz), 4.88 (m, 1H), 4.54 ( m, 2H), 3.91 (r, 3H), 3.36 (m, 2H), 3.07 (s, 6H), 2.84 (s, 3H), 2.32 (m, 2H). 2.09 (m, 2H). ÍR (my roscope) 2920, 1715, 1695, 1630, 1435, 1390, 1270, 1 190 cm-1. MS (DCI / NH3) 489 (M + H) +. Anal fell. ara • HCl • 3 H20: C, 53.93; H, 6.09; N, 14.51. Enct "" C, 54.09; H, 5.86; N, 13.92.
Example 5 Preparation of 4-methyl ester hydrochloride of 1-dimethyl amide of l-N, N-dimethylcarbamoyl-4-methoxycarbonyl-3-. { f4- (lH-2-methylimidazo-f4.5-c] pyrid-1-yl) -piperidin-1-ill carbonyl} indole-1, 4-dicarboxylic acid The desired compound was prepared according to the method of Example 1, with the exception that 4-methyl amide-1-dimethyl ester of indole 1,3,4-tricarboxylic acid (Indole 3 ). to replace the 1- (dimethyl) amide of 6- (4-fluorophenyl) indole-1,3-dicarboxylic acid, and because 1H-1- (piperidin-4-ylmethyl) -2-methyl [4.5c] imidazopyridine was used ( Amine 2) to replace 1H-1- (piperidin-4-yl) -2-methyl [4.5c] imidazopyridine (Amine 1). p.f. > 200 ° C (decomposition). : H NMR (DMSO-d6, 300 MHz) d 8.80 (s, 1H), 8.29 (d, 1H, J = 6 Hz), 7.83 (s, 1H), 7.87 (dd, 1H, J = 0.5, 6 Hz) ), 7.63 (m, 2H), 7.40 (t, 1H, J = 6 Hz), 4.53 (m, 1H), 4.16 (d, 1H, J = 7 Hz), 3.83 (m, 1H), 3.73 (s) , 3H), 3.03 (s, 6H), 2.69 (m, 2H), 2.61 (s, 3H), 2.16 (m, 1H), 1.60 (m, 2H), 1.22 (m, 2H). IR (KBr) 3440, 2940, 2775, 1690, 1640, 1620, 1440, 1390 cm-1. MS (DCI / NH3) m / e 503 (M + H) +.
Anal. lime. for C27H30N6O4 - HCl 2.75 H20: C, 55.10; H, 6.25; N, 14.28. F'ncom
C, 55.32; H, 6.72; N, 13.72.
Example 6 Preparation of dimethyl amide hydrochloride of 6- (4-fluorophenyl) -3- acid. { r4- (1H-2-methylimidazo-r4.5-clpyrid-1-yl) -methylpiperidin-1-illcarboni-1-indole-1-carboxylic acid The desired compound was prepared according to the method of Example 1, except that the used 1H-1- (piperidin-4-ylmethyl) -2-methyl [4.5c] imidazopyridine (Amine 2) to replace 1H-1- (piperidin-4-yl) -2-methyl [4.5c] -imidazopyridine (Amine 1),: H NMR (DMSO-d6, 300 MHz) OR 8.79 (s, 1H) .8.29 (d, 1H, J = 6 Hz), 7.88 (s, 1H), 7.80 (d, 1H, J = 1 Hz), 7.73 (m, 3H), 7.66 (dd, 1H, J = 1, 3 Hz), 7.52 (dd, 1H, J = 2, 5 Hz), 731 (m, 2H), 4.18 (d , 2H, J = 9 Hz), 3.83 (m, 2H), 3.03 (s, 6H), 2.69 (m, 2H), 2.61 (s, 3H), 2.16 (m, 1H), 1.60 (m, 2H) , 1.22 (m, 2H). IR (m.crowp.0 3400, 2930, 1685, 1615, 1515, 1475, 1440, 1385 cnr 1. MS (DCI / NH3) m / e539 (M + H) +, 231 Anal.c. for C31H3? FN6? 2 • HCl • 3.25 H20: C, 58.76; H, 6.12; N, 13.26, Found C, 58.76; H, 6.28; N, 12.88.
Example 7 Preparation of dimethyl amide hydrochloride of 4-chloro-3-l r4- (lH-2-methylimidazo- [4,5-c] pyrid-1-yl) -methylpiperidin-1-yl] -carbonyl} Indole-l-carboxylic acid The desired compound was prepared according to the method of Example 1, with the exception that 1-dimethyl amide of 4-chloroindol-1,3-dicarboxylic acid (Indole 4) f lourofeni I) indole was used -1, 3 -dicarboxylic acid, and 1H-1- (piperidin-4-lmethyl) -2 -methyl [4. 5c] imidazopyridine (Amin 2) to replace the 1H-1- (piperidin-4-yl) -2-methyl [4. 5c] -imidazopyridine (Amine 1).
X H NMR (DMSO-dd, 300 MHz) d 8.78 (s, 1 H), 8.27 (d, 1 H, J = 6 Hz), 7.79 (s, 1 H), 7.58 (m, 2 H). 1.17 (m, 2H), 4.14 (d, 2H, J = 9 Hz), 3.53 (m, 2H), 3.03 (s, 6H), 2.67 (m, 2H), 2.63 (s, 3H), 2.16 (m, 1H). 1.40 (m, 2H), 0.99 (m, 2H). IR (KBr) 3440 (br), 2930, 1695, 1630, 1390, 1 180 crn "1. MS (ÜCI / NH3) e 479, 481 (M + H) + A" * "1 tj | PJ ™
C25H27ClN6? 2-HCl: C, 58.26; H, 5.48; N, 16.30. Encont C, 53.3 i; H. 7.22. N, 13.15.
Example 8 Preparation of l- (2-ethoxyethyl) -6- (4-fluorophenyl) -3- hydrochloride. { r - (lH-2-methylimidazo-r4.5-c) pyrid-l-yl) -methylpiperidin-l-yl-1-carbonyl indole
Step i; 6- (4-fluorophenyl) -3-t4- (lH-2-methylimidazo-r.5-clpyrid-1-yl) -methylpiperidin-1-yl} -carbonil} Indole The desired compound was prepared according to the method of Example 1, with the exception that 6- (4-fluorophenyl) indole 3-carboxylic acid (Indole 2) was used to replace the 1-dimethyl acid amide of 6- (4-fluorophenyl) indole-1,3-dicarboxylic acid, and lH-l- (piperidin-4-ylmethyl) -2-methyl [4,5-c] imidazopyridine (Amine 2) was used to replace 1H-1- ( piperidin-4-yl) -2-methyl [4,5-c] imidazopyridine (Amine 1), and dimethyl formamide was added to the reaction mixture.
Step 2; L- (2-ethoxyethyl) -6- (4-fluorophenyl) -3- (r4- (lH-2-methylimidazo-r4.5-clpyrid-l-yl) -methylpiperidin-l-yl -carbonyl] hydrochloride. indole to a solution in dimethyl formamide (6 milliliters) of 6- (4-fluorophenyl) -3- { [4-lH-2-methylimidazo- [4,5-c] pyrid-1-yl) -piperidine- 1-yl] -carbonyl} indole (0.017 grams, 0.23 millimoles), prepared as in Step 1, NaH (0.010 grams, 0.40 millimoles) was added. After 5 minutes, a solution of 2-bromoethylethyl ether (0.042 grams, 0.27 mmol) in dimethyl formamide (2 milliliters) was added and the reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and brine. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a brown liquid. The crude product was taken up in tetrahydrofuran, and treated with 4 N HCl / dioxane (0.10 milliliters). The hydrochloride salt was isolated as a white powder by dilution with ether, filtration, and vacuum drying. X H NMR (DMSO-d 6, 300 MHz) d 9.35 (s, 1 H), 8.64 (d, 1 H, J = 6 Hz), 8.38 (s, 1 H), 7.84 (bds, 1 H), 7.77 (m, 3 H) , 7.73 (dd, 1H, J = 1, 3 Hz), 7.42 (dd, 1H, J = 2.5 Hz), 7.29 (m, 2H), 4.47 (d, 2H, J = 9 Hz), 4.38 ( m, 2H), 3.83 (m, 4H), 3.42 (q, 2H, J = 7 Hz), 2.89 (ra, 2H), 2.77 (s, 3H), 2.22 (m, 1H), 1.55 (m, 2H ), 1.40 (m, 2H), 1.02 (t, 3H, J = 7 Hz). IR (KBr) 2920, 2850, 1655, 1635 cm-1. Anal. I fell for C32H3- ^ N5? 2F • 2 HCl • 1.25 H20: C, 60.52; H, 6.1 1; N, 1 1.03 Encone. C, 60.47; H, 6.01; N, 1 1.58.
Example 9 Preparation of l- (2-ethoxyethyl) -4-chloro-3-f f4- (lH-2-methylimidazo-r4.5-cTPridid-l-yl) -methylpiperidin-l-yl hydrochloride} -carbonillindol
Step i; 4-chloro-3-. { r4- (lH-2-methylimidazo-r4.5-clpyrid-l-iD-methylpiperidin-1-yl)) -carbonyl.} indole To a solution in methanol (10 milliliters) of dimethyl amide hydrochloride of 4 -chloro-3- { [4-1H-2-methylimidazo- [4,5-c] pyrid-1-yl) -methylpiperidin-1-yl] -carbonyl.} indole 1-carboxylic acid (0.292 grams, 0.61 mmol) ), prepared as in Example 7, was added K2C03 (1.0 grams, 7.2 mmol), and the mixture was stirred at room temperature for 4 days.The reaction mixture was divided between CH2C1 and H20.The organic phase was dried on MgSO4, filtered, and concentrated in vacuo to give 4-chloro-3- { [4-1H-2-methylimidazo- [4,5-c] pyrid-1-yl) -methylpiperidin-1-1] -carbonyl.} indole (0.224 grams) as a yellow oil.
Step 2; L- (2-ethoxyethyl) -4-chloro-3-l G4- (1H-2-methylimidazo-r4.5-C | pyrid-1-yl) -methylpiperidin-1-yl-carbonyl hydrochloride} indole The desired compound was prepared according to the method of Example 8, Step 2, with the exception that it used 4-chloro-3-. { [4-lH-2-methylimidazo- [4,5-c] pyrid-1-yl) -methylpiperidin-1-yl] -carbonyl} indole, prepared as in Step 1, to replace 6- (4-f-lourophenyl) -3-. { [4-1H-2-methylimidazo- [4,5-c] pyrid-1-yl) -piperidin-i-yl] -carbonyl} indole ^ RN (DMSO-d6, 300 MHz) d 9.36 (s, 1H), 8.62 (d.2H, J = 6Hz), 8.31 (d, 1H, J = 6 Hz), 7.56 (d, 1H, J = 6 Hz), 7.50 (s, lH), 7.16 (m, 2H), 4.38 (m, 4H), 3.70 (m, 2H), 3.38 (m, 4H), 2.92 (m, 2H), 2.73 (s, 3H) ), 2.32 (m, 1H), 1.43 (m, 2H), 1.18 (m, 2H), 0.99 (t, 3H, J = 7 Hz). IR (KBr) 3430 (br), 2940, 2860, 1625, 1440 car1. MS (DCI / NH3) 480, 482 (M + H) +. ? n? I fell P r .. C26H30C1N5 2-HCl • 2.5 H20: C, 55.62; H 646- N 1247 ¿...,? '? - O- », 1 .47. cnconL. SSb4 J-T
6. 44; N, 12.18. JB "",
EXAMPLE 10 Preparation of 4-methyl ester of 1-dimethyl amide ester hydrochloride of 3-rf4-f2 (lH-2-methylimidazo- | "4.5-c1pyrid-1-yl) -e.till iperazin-1-yl-carbonate indol-1, 4-dicarboxylic acid The desired compound was prepared according to the method of Example 1, with the exception that 4-methyl ester of 1-dimethyl amide of indole-1,3,4-tricarboxylic acid was used ( Indole 3) to replace the l-dimethyl amide of 6- (4-fluorophenyl) indole-1,3-dicarboxylic acid, and lH-l- [2- (piperazin-1-yl) ethyl] -2- was used methyl [.5-c] imidazo-pyridine (Amine 3) to replace the 1H-1- (piperidin-4-yl) -2-methyl [4,5-c] imidazopyridine (Amine 1).
1 H NMR (DMSO-do, 300 MHz) d 8.79 (s, 1 H), 8.28 (d, 1 H, J = 6 Hz), 7.89 (s, 1 H) ,: 7.87 (d, 1 H, J = 6 Hz), 7.63 (d, 1H, J = 7 Hz), 4.32 (m, 2H), 3.72 (s, 3H), (s, 3H), 2.61 (m, 2H), 2.56 (m, 2H), 2.43 (m, 2H). IR (KBr) 3440, 2950, 1693. 1640, 1435, 1390 cm - '. MSIDCI / NH3) m / e 518 (M + H) +. 246. Anal 1 for C 27 H 31 N 7 O 4 HCl-4 H20: C, 51.80; H, 6.44; N, 15.66. In one c, 51.98; H, 6.12; N, 15.21.
Example 11 Preparation of 1- (dimethyl) amide hydrochloride of 6- (4-fluorophenyl) -3-r acid. { 4-r 2 - (1 H-2-methylimidazole 4,5-c) pyrid-1-yl) -ethyl-1-piperazin-1-yl-carbonyl} - indole-l-carboxylic acid The desired compound was prepared according to
Method of Example 1, with the exception that 1H-1- [2- (piperazin-4-yl) ethyl] 2-methyl [4,5-c] imidazo-pyridine (Amine 3) was used. to replace 1H-1 (piperidin-4-yl) -2-methyl [4.5-c "l imidazopyridine (Amine 1).: H NMR DMSO-do, 300 iMHz) d 8.79 (s, 1H), 8.29 ( d, 1H, J = 6 Hz), 7.89 (s, 1H), 7.81 (bds, 1H), 7.73 (m, 3H), 7.59 (d, 1H, J = 6 Hz), 7.52 (d, 1H, J = 7 Hz), 7 * '(m, 2H), 4.32 (m, 2H), 3.58 (m, 2H), 3.03 (s, 6H), 2.69 (m, 2H), 2.61 (s, 3H), 2.61 (m, 2H), 2.56 (m, 2H), 2.43 (m, 2H) MS (DCI / NH3) m / e 554 (M + H) + Example 12 Preparation of tertiary butyl ester of 6- (4-) acid flourofenil) -3 f T4- (lH-2-methylimidazo- r4.5-clPrid-l-yl) piperidin-l-yl -sulfonyl.} - indole-l-carboxylic acid To a solution under N2 of 1H- 1- (piperidin-4-yl) -2-methyl [4,5-c] imidazopyridine (Amine 1) (76 milligrams, 0.35 mmol) in tetrahydrofuran (2 milliliters) was added triethyl amine (70 microliters), 0.50 millimole), and a solution of tertiary-1-butoxy-carbonyl-6- (4-fluorophenyl) indole-3-sulfonyl chloride (Indole 5) (137 milligrams, 0.33 mmol) in tetrahydrofuran (1.3 milliliters), and the The reaction mixture was stirred for 48 hours at room temperature. The reaction mixture was filtered, and the filtrate was concentrated in vacuo and azeotroped with CH C12, to give an orange foam (220 milligrams). Chromatography on silica gel (40: 1, and then 20: 1 CHCl 3 -methanol) gave tertiary butyl ester of 6- (4-fluorophenyl) -3- acid. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) piperidin-1-yl] sulfonyl} indole-l-carboxylic acid (141 milligrams, 72 percent) as a yellow foam la. 2 H NMR (DMSO-do, 300 MHz) d 1.69 (s, 9 H), 1.89-9
(c, 2H), 2.30 (m, 2H), 2.51 (s, 3H). 2.78 (t, 2H, J = 12 Hz), 4.01 (d, 2H, J = 12 Hz), 4.44 (m, 1H), 7.32 (d, 1 H, J = 5.5 Hz), 7.36 (t, 2H, J (F- Hor », Horto Hmeta) = 8.8 Hz), 7.74 (dd, 1H, J = 1.6, 83 Hz), 7.76 (dd, 2H, J (F-Hmeia," ortho -Hmeta) = 5.5, 8.8 Hz), 8.00 (d, 1H, J = 8.4 Hz), 8.11 (d, 1H, J = 5.5 Hz), 8.25 (s, 1 H), 8.44 (d, 1H, J = 1.5 Hz), 8.75 (s, 1H) IR (microscope) iQ68 (m), 1 148 (s), 1232 (s), 1288 (m), 1362 (s), 1436 cnr1, MS (FAB) m / e 628 (M + K) +, 590 (M + H) +. '^ "" I PdW - C3 iH32N5? FS 0.4 H20: C, 62.38; H, 5.54; N, 1 1.73.? &? N * C ..62.55; H, 5.70; N, 1 1.36 EXAMPLE 13 Preparation of 6- (4-fluorophenyl) -31 T4- (lH-2-methylimidazo- [4,5-clpyrid-1-yl) PIPperidin-1-ill-sulfonyl indole The desired compound was prepared by treating a tetrahydrofuran solution of tertiary butyl ester of 6- (4-fluorophenyl) -3 { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) ) piperidin-1-yl.}. -sulfonyl.} indole-1-carboxylic acid (124 milligrams, 0.21 mmol), prepared As in Example 12, with sodium methoxide (25 percent methanol, 0.20 milliliter, 0.88 millimole). 6- (4-fluorophenyl) -3 was obtained. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl} -sulfonyl} pure indole (51 milligrams, 50 percent) by recrystallization from ethyl acetate, m.p. 176-80 ° C.
XH NMR (DMSO-d6.300 MHz) d 1.82-1.94 (c, 2H), 2.24 (m,
2H), 2.51 (s, 3H), 2.68 (t, 2H, J = 12 Hz), 3.97 (d, 2H, J = 12 Hz), 4.40 (m, 1H), 7.16 (d, 1H, J = 5.5 Hz), 732 (t, 2H, J (F-! HOI to •, Horto. -Hmeta) = 8.8 Hz), 7.53
(dd, 1H, 1.5, 8.5 Hz), 7.74 (dd, 2H, J (F-Hmeta, Horto -Hmeta) = 53, 9.0 Hz),
7. 79 (d, 1H, J = 1.1 Hz), 7.92 (d, 1H, J = 8.5 Hz), 8.08 (d, 1H, J = 5.9 Hz), 8.10
(d, 1H, J = 2.6 Hz), 8.74 (s, 1 H), 1233 (d, 1 H, J = 2.2 Hz). IR (microscope) 93g
(m), 1124 (s), 1137 (s), 1297 (s). 1323 (m), 1362 (m), 1508 (m), 2928 (br), 3168
(br) cm-1. MS (DCI NH3) m / e 490 (M + H) +. Anal. lime. for • C26H24N5O2FS • 1.5
H20: C, 60.45; H, 5.26; N, '3.56 r.ncont. • C, 60.27; H, 5. 19; N, 13.49.
Example 14 Preparation of dimethyl amide hydrochloride of 6- (4-fluorophenyl) -3-174- (iH-2-methylimidazo-r4.5-clpyrid-1-yl) piperidin-γ-yl acid} -sulfonyl > indole-l-carboxylic acid to a solution under N2 of 6- (4-fluorophenyl) -3-. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) piperidin-1-yl] sulfonyl} indole (86 milligrams, 0.18 millimoles), prepared as in Example 13, in tetrahydrofuran (3.6 milliliters), powdered KOH (58 milligrams, 0.90 millimoles) was added, and the reaction mixture was stirred for 45 minutes at room temperature. ambient. Dimethylcarbamyl chloride (33 microliters, 0.36 mmol) was added via syringe, and the reaction mixture was stirred for one hour at room temperature. The reaction mixture was diluted with ethyl acetate, and extracted twice with saturated aqueous NaHCO3. The organic phase was dried over Na 2 SO 4, filtered, and concentrated in vacuo to give a yellow foam (103 milligrams). Chromatography on silica gel (40: 1), and then 20: 1 CHCl 3 -methanol) gave dimethyl amide of 6- (4-fluorophenyl) -3- acid. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) piperidin-1-yl] sulfonyl} indole-l-carboxylic acid (69 milligrams, 69 percent). The hydrochloride salt (52 milligrams, 71 percent) was prepared as described in Example 8, Step 2. p.f. 135-145 ° C.
NMR (DMSO-d6, 300 MHz) d 2.01-2.1 1 (c, 2H), 2.38 (m, 2H), 2.68 (s, 3H), 2.70 (t, 2H, J = 1 1 Hz), 3.10 (s) , 6H), 4.00 (d, 2H, J = 11 Hz), 4.64 (m, 1H), 7.33 (t, 2H, J (F- fiopo -., Hopo -Hmeta) = 8 S Hz), 7.66 (dd) , 1H, J = 1.5, 8.4 Hz), 7.76 (dd, 2H, J (F-Hmeta ,. Hor.o -Hmeta) = 5.5, 8.8 Hz), 7.90 (d, 1H, J = 1.1 Hz). 7.99 (d, 1H, J = 8.1 Hz), 8.22 (d, 1H, J = 6.6 Hz), 8.35 (s, 1 H), 8.50 (d, 1 H, J = 6.6 Hz), 932 (s, 1 H). IR (microscope, i 155 (s)> 1336 (m), 1355 (ni), 1390 (s), 1477 (s), 1517 (s), 1700 (s), 2597 (br), 3401 (br) cpr I. MS (DCI / NH3) m / e 561 (M + H) + (free base) Anal, ct for C29H30N6O3FSCI 1.75 H20: C, 55.41; H, 537; N, 1337. Found C, 55.51; H, 5.41; N, 13.19.
Example 15 Preparation of tertiary butyl ester of 6- f-fluorophenyl) -3-fr4- (lH-2-methylimidazor4.5-cipyrid-l-iDpiperidin-l-ill sulfonyl.) Indole-l-carboxylic acid ester suspension of 1H-1- (piperidin-4-ylmethyl) -2-methyl [4,5-c] imidazopyridine (Amine 2) (69 milligrams, 0.30 mmol) in tetrahydrofuran (1 milliliter) and dioxane (1 milliliter), was added triethyl amine (0.60 milliliters, 0.43 mmol) and a solution of tertiary-1-butoxy-carbonyl-6- (4-fluorophenyl) indole-sulfonyl chloride (Indole 5) (110 milligrams, 0.27 mmol) in tetrahydrofuran (1.6 milliliters), and the reaction mixture was stirred overnight at room temperature, the reaction mixture was diluted with CH2C12, concentrated in vacuo, and azeotroped with CH2C12, chromatography on silica gel (80: 1, then 40: 1, and then 20: 1 of CHCl3-methanol) gave a peach-colored foam that was triturated and dried in vacuo to give tertiary butyl ester of 6- (4-fluorophore) acid. nil) -3- { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) methylpiperidin-1-yl] sulfonyl} -indol-l-carboxylic acid as a peach-colored powder (100 milligrams, 62 percent),: H NMR (DMSO-d6, 300 MHz) d 132-1.57 (c, 4H), 1 (s, 9H), 1.77- 1.91 (c, 1H), 2.31 (t, 2H, J = 11 Hz), 2.51 (s, 3H), 3.75 (d, 2H, J .- 12 Hz) .4.08 (d, 2H, J = 7.4 Hz) , 733 (t, 2H, J (F-ito, Horro. Hmeta) = 8.8 Hz), 7.54 (d, 1H, J = 5.5 Hz), 7.65 (dd, 1H, J = 1.5, 8.5 Hz), 7.72 ( dd, 2H, J (F- Hmeta, "rto .. Hmeta) = 5.5, 8.8 Hz), 7.88 (d, 1H, J = 8.1 Hz), 8.06 (s, 1H), 8.22 (d, 1H, J = 5.5 Hz), 8.34 (d, 1H, J = 1.5 Hz), 8.76 (s, 1H). IR (, microscope :) 8I9 (m), 1068 (m), 1146 (s), 1231 (s), 1286 (m), 1343 (s), 1367 (s), 1475 (m), 1518 (m), 1747 (s) .2935 (), 2980 (w) crir1, MS (DCI / NH3) m / e 604 ( M + H) +. Anal
"1. for - C32H34N5O4FS • 0.5 H20 • 0.2 Et20: C, 61.42; H, 5.67; N, 11.12. Enco C, 61.43; H, 532; N, 11.00
Example 16 Preparation of 6- (4-fluorourenyl) -3-f 4- (lH-2-methylimidazo-r4.5-clpyrid-l-yl) methylpiperidin-l-insulfonyl indole The desired compound was prepared according to method of Example 13, with the exception that tertiary butyl ester of 6- (4-fluorophenyl) -3- acid was used. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) methylpiperidin-1-yl] sulfonyl} indole-1-carboxylic acid (91 milligrams, 0.15 millimole), prepared as in Example 15, to replace 1-N, N-dimethylcarbamoyl-6- (4-fluorophenyl) -3-. { 4- [(1H-2-methylimidazo [4.5-c] pyr id-1-yl) piperidin-4-yl] sulfonyl} indole 6- (4-fluorophenyl) -3- was obtained. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) methylpiperidin-1-yl] sulfonyl} pure indole (51 milligrams, 67 percent) by chromatography on silica gel (40: 1, then 20: 1, and then 10: 1 CHCl 3 -methanol). lNMR (DMSO-d6, 300 MHz) d 1.32-1.55 (c, 4H), 1.71-1.86 (c, 1H), 2.14 (t, 2H, J = 11.8 Hz), 2.51 (s, 3H), 3.70 ( d, 2H, J = 11.8 Hz), 4.06 (d, 2H, J = 7.0 Hz), 7.29 (t, 2H, J (F- n no, i IO? O -Hmeta) = 8.8 Hz), 7.44 (dd , 1H, J = 1.8.8.5 Hz), 7.54 (dd, 1H, J = 0.7, 5.5 Hz), 7.68 (d, 1H, J = 1.1 Hz), 7.70 (dd, 2H, J (F-Hmeta, " «« "-Hmeta) = 5.5, 8.8 Hz), 7.82 (d, 1H, J = 8.5 Hz), 7.94 (s, 1H), 8.22 (d, lli, J = 5.5 Hz), 8.76 (s, 1H) , 12.20 (d, 1H, J = 2.9 Hz). IR (microsco i) 736 (m) .8f l (s), 1142 (s), 1156 (s), 1329 (s), 1399 (m), 1508 (m) .2855 (ra), 2939 (m) , 3090 (m) cm-1. MS (DCINH3) 503 (M + H) +. Anal. "1. for C27H26N5O2FS • H20: C, 62.17; H, 5.41; N, 13.43. cnc nt C.62.15; H, 5.07; N, 13.23.
Example 17 Preparation of dimethyl amide of 6- (4-f luorofenyl) -3- acid. { r 4- (lH-2-methylimidazor 4.5-pyr id-1-yl) methyl-piper id-l-yl] sulfonyl indole-l-carboxylic acid The desired compound was prepared according to the method of Example 14, with the except that 6- (4-f luorofenil) -3- was used. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) methylpiperidin-1-yl] sulfonyl} indole (41 milligrams, 0.81 millimole), prepared as in Example 16, to replace the
6- (4-f luorophenyl) -3-. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) piperidin-1-yl] sulf onyl} indole Chromatography on silica gel (40: 1, then 20: 1 CHCl 3 -methanol) gave dimethyl amide of 6- (4-f luorofenyl) -3- acid. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) methylpiperidin-1-yl] sulfonyl} indole-l-carboxylic acid as a white foam, which was triturated and dried under vacuum to give the free base (34 milligrams, 74 percent) as a white powder.
X H NMR (DMSO-d 6, 300 MHz) d 133-1.57 (c, 4H),
1. 76- 1.92 (c, 1H), 2.27 (t, 2H, J = 1 1.8 Hz), 2.51 (s, 3H), 3.04 (s 6H), 3.74 (d, 2H, J = 1 1.4 Hz), 4.06 (d, 2H, J = 7.4 Hz), 7.30 (t, 2H, J (F-Hrro, 11 () RIO Hmeta) = 9.0 Hz), 7.54 (d, 1 H, J = 5.5 Hz), 7.58 ( dd, 1H, J = 1.6, 8.2 Hz), 7.72 (dd, 2H, J (F-Hmeta, north, Hmeta) = 5.5, 8.8 Hz), 7.82 (d, 1H, J = 1.1 Hz), 7 (d , 1H, J = 8.5 Hz), 8.18 (s, 1H), 8.22 (d, 1H, J = 5.5 Hz), 8.75 (s, 1H). IR (microscope) 821 (m), 1159 (s), 1338 (m). 1353 (m), 1392 (s), 1476 cor1. MS (DCI / NH3) m / e 575 (M + H) +. ?? JI. AC?. pdra C3oH31N6? 3FS • 0.6 H20 • 0.3 Et2Q
C, 61.66; H, 5.84; N, 13.83. In com. c, 61.72; H, 5.52; N, 13.65.
Example 18 Preparation of 6- (4-fluorophenyl) -3-r -r2- dimethyl amide. { lH-2-methylimidazor4.5-clPrid-1-yl) ethy-piperazin-1-ill sulfonylindole-1-carboxylic acid
Step 1; Tertiary butyl ester of 6- (4-fluorophenyl) -3-fr4-r2- (lH-2-methylimidazor4.5-clPyrid-1-yl) ethyllpiperazin-1-ip sulfonyl acid} Indole-l-carboxylic acid. The desired compound was prepared according to the method of Example 15, with the exception that 1H-l- [2- (piperazin-1-yl) ethyl] -2-methyl [4,5-c] imidazopyridine was used.
(Amine 3) to replace lH-l- (piperidin-4-ylmethyl] -2-methyl [4,5-c] imidazopyridine (Amine 2).
Step 2: 6- (4-fluorophenyl) -3-rf4-r2- (lH-2-methylimidazor4.5-c1 pyrid-1-y1) ethyl] piperazin-1-yl] sulfonyl? indole The desired compound was prepared according to the method of Example 16, with the exception that tertiary butyl ester of 6- (4-fluorophenyl) -3- [. { 4- [(2- (lH-2-methylimidazo [.5-c] pyrid-1-yl) ethyl] piperazin-1-yl}. Sulfonyl] indole-1-carboxylic acid, prepared as in Step 1, replace 6- (4-fluorophenyl) -3- { [4- (lH-2-methylimidazo [4.5-c] pyrid-1-yl) methylpiperidin-1-yl] sulfonyl} indole.
Step 3; Dimethyl amide of 6- (4-fluorophenyl) -3-r (4- r (2- (lH-2-methylimidazor4.5-clIrid-1-yl) ethyl-piperazin-1-illsulfonyl}. The desired compound was prepared according to the method of Example 17, with the exception that 6- (4-fluorophenyl) -3- [. {4- [2- (lH-2- methylimidazo [4,5-c] pyrid-1-yl) ethyl] piperazin-1-yl]. sulfonyl] indole, prepared as in
Step 2, to replace 6- (4-fluorophenyl) -3-. { [4- (1H-2-methylimidazo [4.5-c] irid-1-yl) methylpiperidin-1-yl] sulfonyl} - ndol. p.f. 95-105 ° C. : H NMR (DMSO-d6, 300 MHz) d 2.47 (s, 3H), 2.54 (br, 4H), 2.62 (t, 2H, J = 6.2 Hz), 2.93 (br, 4H), 3.05 (s.6H) ), 4.22 (t, 2H, J = 6.2 Hz), 7.32 (t, 2H, J (F- "« "or," «« or Hmeta) = 8.8 Hz), 7.44 (d, 1H, J = 5.5 Hz ), 7.62 (dd, 1H, J = 1.4, 8.2 Hz), 7.76 (dd, 2H, J (F-Hmeta, Horto Hmeta) = 5.5, 8.5 Hz), 7.84 (s, 1H), 7.89 (d, 1H , J = 8.5 Hz), 8.08 (d, 1H, J = 5.2 Hz), 8.23 (s, 1H), 8.71 (s, 1H). IR (m'croscopioi 1 161 (s), 1352 (m), 1391 (s), 1476 (m), 1516 (m), 1702 (s), 2852 (br w), 2934 (br w) cm- '. MS (DCI / NH3) me 590 (M + H) + .. ?? "Cd! Pdrd C30H32N7O3SF - 0.65 H20 - 0.3 Et20: C, 60.09; H, 5.87; N, 15.72.?" ™ t: C, 60.07; H, 590; N, 15.72.
Example 19 Preparation of 6- (4-fluorophenyl) -3-. { 4- (1H-2-methylimidazo-r4.5-clpyrid-1-yl) piperidin-1-ipacetyl > indole To a low N 2 solution of lH-l- (piperidin-4-yl) -2-methyl [4,5-c] imidazopyridine (Amine 1) (100 milligrams, 0.462 mmol) in dimethyl formamide (1 milliliter), was added N, N-diisopropylethyl amine (0.16 milliliters, 0.92 millimoles), and a solution of 6- (4-fluorophenyl) -3-chloroacetylindole (Indol 6) (127 milligrams, 0.441 millimoles) in tetrahydrofuran (2 milliliters) and dimethyl formamide ( 2 milliliters) for 105 minutes. The reaction mixture was stirred overnight at room temperature, and then diluted with ethyl acetate, and extracted twice with aqueous 0.1M NaOH. The organic phase was dried over Na 2 SO 4, filtered, and concentrated in vacuo to give an orange foam (0.18 grams). Chromatography on silica gel (50: 1 of CHCl3-methanol + 0.5% NH40H, then 20: 1 of CHC13-methanol + 0.5% NH4OH, and then 10: 1 of CHC13-methanol + 0.5% NH4OH) percent) gave 6- (4-fluorophenyl) -3-. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole (46 milligrams, 22 percent) as a light orange powder.
X H NMR (DMSO-d 6, 300 MHz) d 1.84-1.94 (c.2H), 232-2.48 (c, 4H), 2.63 (s, 3H, 3. 1 1-3.20 (c, 2H), 3.74 (s) 2H), 430-4.43 (c, 1H), 7.29 (t, 2H.J (F- non J.nono -Hmeta) = 9.0 Hz), 7.49 (dd, 1 H, J = 1.5, 8.5 Hz), 7.64 (dd,
1H, J = 0.7, 5.9 Hz), 7.70 (d, 1H, J = 1. 1 Hz), 7.73 (dd, 2H, J (F-Hmeta .. Horme Hmeta) = 5.4, 9.0 Hz), 8.24 (d , 1H, J = 6.6 Hz), 8.26 (d, 1H, J = 8.5 Hz), 862 (d, 1H, J = 2.9 Hz), 8.80 (s, 1H), 12.02 (br s, 1H). MS (DCI / NH3) m / e 468 (M + tQ *
Anal. lime. pdra C23H26N5O5F • H20: C, 69.26; H, 5.81; N, 14.42. Find C, 69 18;
H, 5.60; N, 1431.
Example 20 Preparation of dimethyl amide of 6- (4-fluorophenyl) -3-fr4- (lH-2-methylimidazor4.5-clPyridol-yl) piperidin-1-yl-acetyl acid} indole-1-carboxylic acid The desired compound was prepared according to the method of Example 14, with the exception that 6- (4-fluorophenyl) -3- was used. { [4- (1H-2-methylimidazo [4.5-c "] pyrid-1-yl) piperidin-1-yl] acetyl} indole, prepared as in Example 19, to replace 6- (4-fluorophenyl) -3- { [4- (lH-2-methylimidazo [4.5-c] pyrid-1-yl) piperidin-1-yl] sulfonyl.] Ndol, and the indole was dissolved in 2: 1 tetrahydrofuran - dimethylformamide XH NMR (DMSO-d6, 300 MHz) d 1.85- 1.94 (c, 2H), 232-2.48 (c, 4H), 2.63 (s, 3H), 3.10-3.19 (c, 2H), 3.14 (s, 6H), 3.79 (s, 2H), 4.31-4.45 (c, 1H), 7.31 (t, 2H, J (F- "° no, Horco -Hmeta) = 8.8 Hz), 7.62 (dd, 1H , J = 1.6, 8.2 Hz), 7.63 (dd, 1H, J = 0.7, 4.8 Hz), 7.75 (dd, 2-, J (F-Hmeta, Horto.Hmeta) = 5.2, 8.8 Hz), 7.82 ( d, 1H, J = 1.1 Hz), 8.25 (d, 1K = 5.5 Hz), 8.32 (d, 1H, J = 8.1 Hz), 8.80 (s, 1H), 8.89 (s, 1H). IR (micros opium 812 (s), 1389 (s), 1481 (m), 1516 (m), 1606 (w), 1658 (w), 1699 (s), 2810 (br), 2931 (br) cm- 1. MS (DCI / NH3) 539 (M + H) +.? N.,.,., C31H3? N6CbF • 0.8 H20.1.5 Et20: C, 67.26; H.6.14; N, 14.80. C.67.27; H, 5.79; N.14.6 i
Example 21 Preparation of 3-Ir4- (lH-2-methylimidazor4. S-clpyrid-l-ippiperidin-1-ylT-acetyl indol-4-sarboxylic acid methyl ester The desired compound was prepared according to the method of Example 19 , with the exception that 4-methoxycarbonyl-3-chloroacetylindole (Indole 7) was used to replace the
6- (4-fluorophenyl) -3-chloroacetylindole, and dimethyl formamide was used instead of 2: 1 tetrahydrofuran-dimethyl formamide. p.f. 186-187 ° C. X H NMR H H NMR (DMSO-d 6, 300 MHz) d 1.85 (d, 2 H, J = 12 Hz), 2.28 (q, 2 H, J = 12 Hz), 2.41 (t, 2 H, J = 11 Hz), 2.61 (s, 3H), 3.07 (d, 2H, J = 11 Hz),
3. 67 (s, 2H), 3.79 (s, 3H), 4.32 (m, 1H), 7.29 (t, 1H, J = 7.6 Hz), 734 (dd, 1H, J = 1.5, 7.4 Hz), 7.57 (dd) , 1H, J = 0.9, 5.7 Hz), 7.66 (dd, 1H, J = 1.6, 7.6 Hz), 8.24 (d, 1H, J = 5.5 Hz), 8.53; d, 1H, J = 2.6 Hz) .8.79 (s, 1H), 12.16 (br s, IB "). IR otoscope; 1113 (rn), 1126 (m), 1294 (m), 1350 (m), 1421 (m), 1436 (m),
1510 (m), 1612 (m), 1653 (s), 1692 (s) .2950 (m), 3111 (m, 3364 (br) cm-1 MS (DCI / NH3) m / e 432 (M + H ) +., \ nai fallen bread, C24H25N5O3 • H 0: C, 64.13- H 6.05, N, 15.58, C, 64.06, H, 6.00, N, 15.44.
EXAMPLE 22 Preparation of 4-methyl ester of 1-dimethyl amide of 3-4- (lH-2-methylimidazor4.5-clpyrid-1-yl) -piper idin-1-yl ~ | -acetyl ester. dicarboxylic The desired compound was prepared according to the method of Example 20, with the exception that 3- methyl acid ester was used. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) -piperidin-1-yl] -acetyl} indole-4-carboxylic acid, prepared as in Example 21, to replace 6- (4-f luorofenyl) -3-. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole p.f. 93-100 ° C.
X H NMR (DMSO-d 6, 300 MHz) d 1.84 (d, 2 H, J = 12 Hz) .2.24 (q, 2 H, J = 12 Hz), 2.41 (t, 2 H, J = 11 Hz), 2.61 (s) , 3H), 3.07 (d.2H, J = 12Hz), 3.12 (s, 6H), 3.69 (s, 2H), 3.80 (s.3H), 4.33 (m, 1H), 7.45 (t.
1H, J = 7.8 Hz), 7.50 (dd, 1H, J = 0.9, 5.7 Hz), 7.51 (dd, 1H, J = 1.5, 7.4 Hz), 7.82 (dd, 1H, J = 1.3, 7.9 Hz), 8.24 (d, 1H, J = 5.9 Hz), 8.73 (s, 1H), 8.78 (d, '1H, J = 0.7 Hz). IR fmicroscop.o) 1111 (m), 1188 (m), 1286 (m) .1358 (m), 1390 (s), 1431 (m), 1606 (w), 1699 (s), 1724 (s), 2948 () cur1. MS (DCI / NH3) m / e 503 (M + H) +. Anal I fell for 27H3oN6? 4 H20: C, 62.29; H, 6.20; N, 16.14. ,: c, n (C, 62.44; H, 5.90; N 16.04.
Example 23 Preparation of l- (2-ethoxyethyl) -3- methyl ester. { r4- (lH-2-methylimidazor4.5-c.) pyrid-1-yl) piperidin-1-ylacetylindol-1-carboxylic acid To a low N 2 solution of 3-methyl ester. { [4- (1H-2-methylimidazo [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole-4-carboxylic acid (1.00 grams, 2.32 mmol), prepared as in Example 21, in dimethyl formamide, NaH (95 percent, 71 milligrams, 2.8 mmol) was added. After stirring for 20 minutes, 'N, N-diisopropylethyl amine (1.2 milliliters, 6.9 millimoles) and a solution of 2-bromoethylethyl ether (0.44 milliliters, 3.5 millimoles) in dimethyl formamide (4 milliliters) added by drip were added. . The reaction mixture was stirred for 27 hours at room temperature, and then diluted with ethyl acetate, and washed twice with 0.1 M aqueous NaOH. The aqueous phase was brought to a pH of 12 with 1 M aqueous NaOH, and extracted with ethyl acetate. The process was repeated, and the combined organic layers were dried over Na 2 SO 4, filtered, and concentrated in vacuo to give a light orange oil (0.36 grams). Chromatography on silica gel (40: 1 CHCl3-methanol + 0.5% NH4OH, and then 20: 1 CHCl3-methanol + 0.5% NH4OH) gave l- (2-ethoxyethyl) 3-methyl ester -. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole-l-carboxylic acid (1.01 grams, 86 percent) as a pale yellow powder. 1H ^ (DMS (d6 3 (?)
MHz) d 1.00 (t, 3H, J = 7.0 Hz), 1.84 (d, 2H, J = 11 Hz) .2.29 (q, 2H, J = 11 H), 2.39 (t, 2H, J = 11 Hz) ), 2.61 (s, 3H), 3.05 (d, 2H, J = 10 Hz), 3.40 (q, 2H. = 7.0 Hz), 3.62 (s.2H), 3.78 (t, 2H, J = 5 Hz) , 3.79 (s.3H), 4.33 (m, 1H), 451 (t 2H i = 5.2 Hz), 731-7.40 (c, 2H) .7.58 (dd, 1H.J = 0.8, 5.6 Hz) .7.82 ( dd 1H J - 2.1, 7.0 Hz), 8.24 (d, 1H, J = 5.5 Hz), 8.60 (s, 1H), 8.79 (s, 1H). IR cmicroxop? O) 1114 (s), 1198 (m) .1286 (s) .1360 (m) .1394 (s), 1435 (m), 1524 (s), 1607 (n) 1651 (m) .1723 (s), 2949 (m), 3394 (br) cpr. MS (DCI / NH3) me 504 (M + H) * '
Anal. lime. For C28H33N5O4-1.5 H20: C, 63.38; H, 6.84; N, 13.20. n ^ < 63.64; H.6.42; N, 12.79.
Example 24 Preparation of 4-chloro-6-3-. { r 4 - (lH-2-methylimidazo-4,5-cTpyrid-1-yl) piperidin-1-illacetyl > Indole The desired compound was prepared according to the method of Example 19, with the exception that 4-chloro-3-chloroacetylindole (Indole 8) was used to replace 6- (4-fluorophenyl) -3-chloroacetylindole.
1 H NMR (DMSO-d 6, 300 MHz) d 1.87 (d, 2 H, J = 12 Hz), ~ 2.30 (q, 2 H, J = 13 Hz), 2.46 (t, 2 H, J = 12 Hz), 2.63 ( s, 3H), 3.12 (d, 2H, J = i2 Hz), 3.77 (s, 2H), 4.34 (m, 1H), 7.20 (d, 1H, J = 2.9 Hz) .7.21 (d, 1H, J = 5.9 Hz), 7.48 (dd, 1H, J = 3.1, 6.0 Hz) .7.56 (dd, 1H, J = 0.9, 5.7 Hz), 8.22 (d, 1H, J = 5.5 Hz), 8.48 (s, 1H ), 8.79 (d, 1H, J = 0.7 Hz), 12.16 (br s, 1H). IR (microscope) 740 (m), 1 J 09 (s) .1291 (m), 1308 (m), 1360 (), 1388 (m), 1414 (s), 1434 (m) .1451 (m), 1468 (m) .1520 (m), 1610 (m) .1661 (s), 2813 (m), 2931 (m), 3154 (br) cm-1. MS (DCI / NH3) m / e 408.410 (M + H) +. Anal. lime. for C22H22N5OCI • 1.75 H20: C, 60.13; H, 5.84; N, 15.93 E "8pt.c, 6036; H, 5.48; N, 15.56.
EXAMPLE 25 Preparation of l- (2-ethoxyethyl) 4-chloro-3- (T4- (1H-2-menelimidazor. 5-clPirid-1-yl) piperidin-1-yl.} Acetyl.} Indole The desired compound was prepared according to the method of Example 23, with the exception that 4-chloro-3 { [4- (lH-2-methylimidazo [4.5-c] pyrid-1-yl) piperidin was used. -l-yl] acetyl, indole, prepared as in Example 24, to replace the methyl ester of 3- {[4- (lH-2-methylimidazo [4.5-c] pyrid-1-yl)) piperidin-1-yl] acetyl, 4-indole-4-carboxylic acid, page 59-65 ° C.
X H NMR (DMSO-d 6, 300 MHz) d 1.01 (t, 3 H, J = 7.0 Hz), 1.86 (d, 2 H, J = 12 Hz). 230 (q.2H, J = 12 Hz), 2.44 (t, 2H, J = 11 Hz). 2.62 (s, 3H), 3.10 (d, 2H J = 11 Hz), 3.40 (q, 2H, J = 7.0 Hz), 3.74 (s 2H), 3.76 (t, 2H, J = 5.4 Hz), 4.34 (m, 1H), 4.46 (t, 2H, J = 5.4 Hz). 7.24 (d, 1H, J =? .8 Hz). 7.26 (d, 1H, J • = 7.4 Hz), 7.54 (d, 1H, J = 5.5 Hz), 7.62 (dd, 1H, J = 2.0, 7.2 Hz), 8.22 (d, 1H, J = J 9 Hz ), 8.50 (s, 1H), 8.79 (s, 1H). IR (i roscopi) 1089 (m), 1 1 15 (s), 1290 (m), 1359 (s). 1394 (s), 1435 (s), 1468 (m), 1523 (s), 1607 (m), 1659 (s), 2808 (w), 2866 (w). 2934 (w), 2972 (w), 3392 (br) cm-1. MS (DCI / NH3) m / e 480 (M + H) + nal cal for C26H30N5Q2CI • 0.75 H20: C, 63.28; H, 6.43; N. 14.19. Lnc? N, c.
6332; H, 6.61; N, 14.18.
EXAMPLE 26 Preparation of dimethyl amide of 4-chloro-3- (T4- (1H-2-methyl imidazof 4.5-c 1 -pyrid-li Dpiper idin-1-ill acetyl} indole-l-carboxylic acid The desired compound was prepared according to the method of Example 20, with the exception that 4-chloro-3-. {[[4- (lH-2-methylimidazo [4.5-c] pir id-1-yl) piperidin- 1-yl] acetyl, indole, prepared as in Example 24, to replace 6- (4-fluorophenyl) -3-. {[[4- (lH-2-methylimidazo [4.5-c] pyrid- 1-yl) piperidin-1-yl] acetyl, indole, mp 79-83 ° C.
* H NMR (DMSO-d6, 300 MHz) d 1.86 (d, 2H, J = 12 Hz), 2.26 (q, 2H, J = 12 Hz), 2.45 (t, 2H, J = 11 Hz), 2.61 ( s, 3H), 3.09 (s, 6H), 3.11 (d, 2H, J = 11 Hz), 3.80 (s, 2H), 434 (m, 1H), 7.35 (d, 1H, J = 2.6 Hz), 736 (d, 1H, J = 6.6 Hz), 7.47 (dd, 1H, J = 1.1, 5.5 Hz), 7.62 (dd, 1H, J = 2.8, 6.4 Hz), 8.22 (d, 1H, J = 5.9 Hz ), 8.63 (s, 1H), 8.78 (d, 1H, J = 0.7 Hz). IR (microscope) 1106 (m), 1184 (m), 1359 (m), 1390 (s), 1426 (m), 1468 (m), 1524 (w), 1607 (w), 1700 (s), 2935 (), 3392 (br) cm-1. MS (DCI / NH3) m / e 479 (M + H) +. Anal. lime. for r C35H27N6Q2CI • 0.5 H20: C, 61.53; H, 5.7S; N, 17.22. In com. C.61.32; H, 5.79; N, 16.87.
Example 27 Preparation of 4-methyl-3-. { r 4 - (1 H-2-methylimidazo-4,5-c1pyrid-1-yl) piperidin-1-ill acetyl} Indole The desired compound was prepared according to the method of Example 19, with the exception that 4-methyl-3-chloroacetylindole (Indole 9) was used to replace 6- (4-fluorophenyl) -3-chloroacetylindole, and added the indole solution in dimethyl formamide to the reaction mixture during
minutes, p.f. 118-128 ° C. 2 H NMR (DMSO-d 6, 300 MHz) d 1.88 (d, 2 H, J = 11 Hz), 234 (q, 2 H, J = 12 Hz), 2.46 (t, 2 H, J = 11 Hz), 2.63 (s) 3H). 2.71 (s 3 H), 3. 14 (d, 2 H, J = 1 1 Hz), 3.77 (s, 2 H), 435 (m, 1 H), 6.92 (d. 1 H, J = 7.0 Hz). 7.10 (t, 1H, J = 7.8 Hz), 730 (d, 1H, J = 8.1 Hz), 7.62 (dd, 1H, J = 0.7, 5.5 Hz). 8.23 (d, 1H, J = 5.5 Hz), 8.48 (s, 1H), 8.79 (s, 1H), 1 1.89 (brs.1H). IR (- my roscope) n i3 (m), 1362 (m), 1402 (s), 1436 (m), 1520 (). 1610 (m), 1651 (s), 2808 (br), 2950 (br), 3271 (br) cm-1. MS (DCI / NH3) m / e 388 (M + H) +. Anuí 'fell. for C23H25N5O-H20 • 0.2 CH2C12: C, 65.96; H, 6.54; N, 16.58. .-pcom / • _. 65.95; H, 6.39; N, 16.48.
Example 28 Preparation of l- (2-ethoxyethyl) -4-methyl-3-lf4- (lH-2-methylimidazo 4.5-c) pyrid-l-yl) piperidin-l-illacetill indole The desired compound was prepared from according to the method of Example 23, with the exception that 4-methyl 3- was used. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole, prepared as in Example 27, to replace the methyl ester of 3- acid. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) piperidin-1-yl] acetyl} Indole-4-carboxylic acid. ! H NMR (DMSO-d6, 300 MHz) d 1.04 (t, 3H, J = 7.0 Hz), 1.89 (d, 2H, J = 11 Hz), 236 (q 2H, J = 11 Hz), 2.45 (t , 2H, J = 1 1 Hz), 2.63 (s, 3H), 2.71 (s, 3H), 3.14 (d, 2H, 3 = 10 Hz), 3.42 (q, 2H, J = 7.0 Hz), 3.74 ( s, 2H), 3.77 (t, 2H, J = 5.5 Hz), 436 (m, 1H), 4.43 (t, 2H, J = 5.3 Hz), 6.97 (d, 1H, J = 7.0 Hz), 7.15 ( t, 1H, J = 7.8 Hz), 7.42 (d, IH, J = 8.1 Hz) .7.63 (dd, 1H, J = 1.0, 5.7 Hz), 8.23 (d, 1H, J = 55 Hz), 8.53 ( s, 1H), 8.79 (s, 1H). IR (microscope) 1112 (s) .1288 (m), 1358 (s), 1390 (sj, 1432 (m), 1465 (m), 1523 (s), 1606 (m), 1649 (s), 2807 ( ) .2865 (w), 2929 (vv) cm "1. MS (FAB) m / e 460 (m + l) +. Anal caled for C27H33N5O2 • 0.5 H2O C, 69.20; H, 7.31; N, 14.94. : C, 6939; H, 7.10; N, 14.82.
Example 29 Preparation of dimethyl amide of 4-methyl 3-f r 4 - (1 H-2-methylimidazor 4,5-clpyrid-1-yl) piperidin-1-ill acetyl} Indole-l-carboxylic acid The desired compound was prepared according to the method of Example 20, with the exception that 4-methyl-3- was used. { [4- (lH-2-methylimidazo [4.5-c] pyr id-1-yl) pipe idin-l-yl] acetyl} indole, prepared as in Example 27, to replace 6- (4-f luorofenyl) -3-. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole, and the indole starting material was dissolved in tetrahydrofuran / dimethyl formamide. : H NMR (DMSO-d6, 300 MHz) d 1.88 (d, 2H, J = 12 Hz), 232 (q, 2H, J = 12 Hz), 2.46 (t, 2H, J = 11 Hz), 2.63 (s, 3H), 2.66 ( s.3H) .3.09 (s.6H) .3.14 (d.2H.J = 11 Hz), 3.81 (s, 2H), 436 (m, 1H), 7.06 (d.1H.J = 7.4 Hz), 7.24 (t, 1H, J = 7.8 Hz), 7.44 (d, 1H, J = 8.1 Hz), 7.58 (dd, 1H, J = 1.0, 5.8 Hz), 8.23 (d, 1H, J = 5.8 Hz), 8.69 (s, 1H), 8.79 (s.1H). (microscope) 721 (m), 1134 (s), 1186 (s), 1200 (s) .1433 (m) .1553 (s), 1616 (s), 1675 (s), 2760 (m), 2866 ( m), 2988 (m) c -1. MS (FAB) m / e 459 (M + 1) +. ? pai cal. for C 6H3? N6? 2 • H20: C.65.53; H, 6.77; N, 17.63. Ell8nt c 65.46, H. 6.62; N, 17.89.
Example 30 Preparation of 4-methyl amide ester hydrochloride
1-dimethyl acid 3-. { trans-4-r (lH-2-methylimidazo-T4.5-clpyrid-l-yl) methylcyclohex-l-yl-1-carbonyl} indole-1,4-dicarboxylic
Step 1: Trans-4 - (N-carbobenzyloxy) aminomethyl-1-cyclohexanecarboxylic acid. To a solution at 0 ° C of trans-4-aminomethyl-1-cyclohexanecarboxylic acid (6.28 grams, 0.04 moles) in 10 percent aqueous NaOH (16 milliliters), benzyl chloroformate (8.29 grams, 0.049) was added dropwise. moles), and 10 percent aqueous NaOH (20 milliliters). The cold bath was removed, and the reaction mixture was stirred vigorously for one hour. The thick white paste was stirred with aqueous 1M HCl (100 milliliters), and the white solid was isolated by filtration, washed with H0, and dried overnight under vacuum to give trans-4- (N-carbobenzyloxy) acid. aminomethyl-1-cyclohexane-carboxylic acid.
Step 2; Trans-4- (N-carbobenzyloxy) aminomethyl-1-cyclohexanecarbonyl chloride. A mixture of trans-4- (N-carbobenzyloxy) -aminomethyl-1-cyclohexanecarboxylic acid (5.02 grams, 17.3 mmol), prepared as in Step 1, and thionyl chloride, was heated at 40 ° C for 30 minutes. The reaction mixture was cooled to room temperature, and diluted with pentane (50 milliliters). Trans-4- (N-carbobenzyloxy) -aminomethyl-1-cyclohexanecarbonyl chloride (4.37 grams) was isolated by filtration and dried in vacuo.
Step 3: 3-r (Trans-l- (N-carbobenzyloxy) -aminomethyl-cyclohex-4-yl) carbonyl] -indole-4-carboxylic acid methyl ester. To a solution of indole-4-carboxylic acid methyl ester (2.33 grams, 13.3 mmol) in CH2C12 (25 milliliters), ethylmagnesium bromide (3 M in ether, 4.4 milliliters, 13.2 mmol) was added. The reaction mixture was stirred for five minutes, and ZnCl 2 (1 M in ether, 40 milliliters, 40 mmol) was added, and the brown nebulous suspension was stirred for 15 minutes. A solution of trans-4- (N-carbobenzyloxy) aminomethyl-1-cyclohexanecarbonyl chloride (4.36 grams, 14.1 mmol), prepared as in Step 2, in CH2C12 (20 milliliters) was added, and the reaction mixture was stirred for three hours. The reaction mixture was poured into a separatory funnel containing saturated aqueous NH 4 Cl, which left a green-chestnut gum. The gum was broken by trituration with aqueous 1M HCl, and CH2C12 / methanol was added to the separatory funnel. The layers were separated and the organic phase was washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica gel (1 percent, then 3 percent methanol / CH2Cl2) gave 3- [(trans s - - (N-carbobenzyloxy) aminomethylcyclohex-1-yl) carbonyl] indole-4-methyl ester -carboxylic (2.83 grams, 48 percent) as a tan foam.
Step 4; 4-methyl ester of 1-dimethyl amide of 3- f (trans-1- (N-carbobenzyloxy) -aminomethylcyclohex-4-yl) carbonyl-1-indol-1,4-dicarboxylic acid. The desired compound was prepared by treating a tetrahydrofuran solution of 3- [(trans-4- (N-carbobenzyloxy) aminomethyl-cyclohex-1-yl) carbonyl] indole-4-carboxylic acid methyl ester, prepared as in Step 3, with KOH and dimethylcarbamyl chloride as described in Example 14.
Step 5; 4-methyl ester of 1-dimethyl amide of 3- f (tra.ns-l-aminomethyl-cyclohex-4-yl) carbonyl] indol-1,4-dicarboxylic acid. The desired compound was prepared by catalytic hydrogenation (10 percent Pd / C, 4 atmospheres of H, ethanol, 17 hours) of 4-methyl ester of 1-dimethyl amide of 3- [(trans-1- (N- carbobenzyloxy) -aminomethylcyclohex-4-yl) carbonyl] indole-1,4-dicarboxylic acid.
Step 6: 4-methyl amide 1-dimethyl acid of 3- r (trans-l- (N-3-nitropyrid-3-yl) aminomethylcyclohex-4-yl) carbonyl indol-1,4-dicarboxylic acid. A mixture of 3- [(trans-1-aminomethylcyclohex-4-yl) carbonyl] indole-1,4-dicarboxylic acid amide-1-dimethyl ester ester (1.04 grams, 2.70 mmol), prepared as in Step 5, and 4-ethoxy-3-nitropyridine (0.485 grams, 2.89 mmol) in CH3CN (10 milliliters) was heated at reflux for 40 hours, and then at 100 ° C for a sufficient amount of time to distill off the solvent. The residue was cooled to room temperature, and dried under vacuum to give a yellow foam (1.44 grams), which was used without further purification.
Step 7: 4-Methyl-1-dimethyl amide of 3- [(trans-l- (3-aminopyrid-4-yl) aminomethyl-cyclohex-4-yl) carbonyl-1-indol-4-dicarboxylic acid. To a solution of 3- [(trans-1- (N-3-nitropyrid-3-yl) aminomethylcyclohex-4-yl) carbonyl] indol-1,4-dicarboxylic acid 4-methyl ester of 1-dimethyl amide. 0.93 grams), prepared in Step 6, in methanol (15 milliliters), SnCl2 (1.9 grams, 10 mmol) was added. Methylene chloride (5 milliliters) was added to give a homogeneous solution, and the reaction mixture was stirred for four hours at room temperature. The reaction mixture was stirred with a regulator with a pH of 7 and CH2C12. The resulting emulsion was broken by filtration, and the organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give a yellow foam that did not contain any of the desired product. The filtration solids were suspended in 5 percent methanol / CH2Cl2, and stirred for 20 minutes, and filtered. The filtrate was concentrated in vacuo to give 3- (trans-1- (3-aminopyrid-4-yl) aminomethyl-cyclohex-4-yl) carbonyl] indole-4-methyl ester of 1-dimethyl amide. dicarboxylic (109 milligrams) as a pale yellow foam.
Step 8; 4-Methyl-1-dimethyl amide ester hydrochloride of 3-r (tra.ns-4-r (1H-2-methylimidazo T4.5-clpyrid-1-yl) methylcyclohex-1-yl] carbonyl}. indole-4-dicarboxylic acid A mixture of 3- [(trans-l- (3-aminopyrid-4-yl) aminomethyl-cyclohex-4-yl] carbonyl] -indolyl ester 4-methyl ester of 3-dimethyl acid , 4-dicarboxylic (105 milligrams), prepared as in Step 7, acetic anhydride (2 milliliters, and acetic acid (4 milliliters), was heated at 125 ° C for 20 hours.The reaction mixture was cooled to room temperature The solvents were removed in vacuo, and the residue was partitioned between CH2C12 and saturated aqueous NaHCO3, The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give a brown oil (68 milligrams). The oil was dissolved in tetrahydrofuran (3 milliliters) and 4 N HCl / dioxane (50 microliters) was added The resulting white precipitate was filtered, washed with ether, and dried under vacuum. or to give hydrochloride 4-methyl ester 1-amide of 3- dimetílica. { [trans -4- [(1H-2-methylimidazo [4.5-c] pyrid-1-yl) methylcyclohex-1-yl] carbonyl} indole-1, 4-dicarboxylic (12 milligrams).
H NMR (D3COD.300 MHz) d 9.19 (s, 1H), 8.57 (d .IH). 839 (s, 1H), 8.26 (m, 1H) .7.75 (d, 1H), 7.43 (m, 2H), 4.35 (m, 2H), 3.80 (s, 3H) .3.01 (s, 6H), 2.82 (s, 3H), 2.81 (m, 1H), 2.02 (m, 2H), 1.77 (, 1H), 1.8 (m, 4H), 1.24 (m, 2H). MS (DCI / NH3) m / e 502 (m + H) +, 244.
Example 31 Preparation of 4- (fur-2-yl) -3- acid. { [- (1H-2-methylimidazor4.5-c] pyrid-1-yl) methylpiperidin-1-illcarbonylindole-1-carboxylic acid
Step 1; Dimethyl amide of 4-bromo-3-y (4- (1H-2-methylimidazor4.5-c.) Pyrid-1-yl) methyl-1-piperidin-1-ylcarbonyl} indole-1-carboxylic acid. desired is prepared according to the method of Example 6, with the exception that 4-bromoindol-3-carboxylic acid (Indole 10) is used to replace 6- (flurophenyl) indole.
Step 2; Dimethyl amide of 4- (fur-2-yl) -3-T4- (lH-2- methylimidazor4.5-c1 irid-l-yl) methylpiperidin-1-incarbonyl acid} Indole-l-carboxylic acid. The desired compound is prepared by heating a dioxane solution of dimethyl amide of 4-bromo-3- acid. { [4- (lH-2-methylimidazo [4.5-c] pyrid-1-yl) methylpiperidin-1-yl] carbonyl} indole-l-carboxylic acid, prepared as in Step 1, tri (normal butyl) - (fur-2-yl) estanne, and tetrakis (triphenylphosphine) palladium (O) catalytic in a sealed tube, for a sufficient amount of time to consume substantially all of the starting material, followed by cooling to room temperature, filtration and chromatography on silica gel.
Example 32 Preparation of 4- (thien-2-yl) -3- acid. { [4- (lH-2-methylimidazor4,5-clpyrid-l-yl) methylpiperidin-1-yl] carbonyl} indole-l-carboxylic acid The desired compound is prepared according to the method of Example 31, with the exception that tri (normal butyl) - (thien-2-yl) is used to replace tri (normal butyl) - ( fur-2-yl) stannane.
EXAMPLE 33 Preparation of 4-ethynyl-3- (f4- (lH-2-methylimidazor4.5-c1pyrid-yl) -methylperidin-l-1-carbonyl-indole-l-carboxylic acid
Step 1; 4- (Trimethylsilylethynyl) -3- acid. { 4- (lH-2-methylimidazor4.5-clpyrid-1-yl) methylpiperidinyl-ill carbonyl} indole-l-carboxylic acid The desired compound is prepared according to the method of Example 31, with the exception that trimethyl- (trimethylsilylethynyl) stannane is used to replace tri (normal butyl) - (fur-2-yl) stannane, and using toluene to replace dioxane.
Step 21: 4-Ethynyl) -3-T-T4- (lH-2-methylimidazor4.5-c1pyrid-1-yl) methylpiperidin-1-in-carbonyl acid} Indole-l-carboxylic acid. The desired compound is prepared by treatment of a tetrahydrofuran / CH3CN solution of 4- (trimethylsilylethynyl) -3- acid. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) methylpiperidin-1-yl] carbonyl} indole-l-carboxylic acid, prepared as in Example 33, with CsF, at room temperature.
EXAMPLE 34 Preparation of dimethyl amide of 4-methoxy-3-f r4- (lH-2-methylimidazor4.5-cl-pyrid-1-yl) -methylpiperidin-1-yl-T-carbonylindole-l-carboxylic acid The desired compound is prepared in accordance with the method of Example 6, with the exception that acid is used
4-methoxyindole-3-carboxylic acid (Indole 11) to replace 6- (4-fluorophenyl) indole.
EXAMPLE 35 Preparation of dimethyl amide of 4-hydroxy-3-lf4- (lH-2-methylimidazor4.5-clPrid-1-yl) -methylpiperidin-1-ipcarbonyl-Indole-1-carboxylic acid The desired compound is prepared by the reaction of a CH2C12 solution of dimethyl amide of 4-methoxy-3- acid. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) -methyl-piperidin-1-yl] carbonyl} indole-1-carboxylic acid, prepared as in Example 34, with BBr3.
Example 36 Preparation of dimethyl amide of 4- (NN-dimethylaminocarbonyloxy-3 { R4- (lH-2-methylimidazo-r.5-c1-pyrid-1-yl) -methylpiperidin-1-yl} -carbonyl Indole-1-carboxylic acid The desired compound is prepared by the reaction of dimethyl amide of 4-hydroxy-3 { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) -methylpiperidin-1-yl] carbonyl.} indole-l-carboxylic acid, prepared as in Example 35, with NaH and dimethylcarbamyl chloride.
Example 37 Preparation of dimethyl amide of 4- (N-dimethylaminocarbonylamino) -3- T4- (1H-2-methylimidazo- [4,5-clpyrid-1-yl] -methylpiperidin-1-yl] carbonyl acid} indole-l-carboxylic
Step 1; 4- (N, N-dimethylaminocarbonylamino) indole The desired compound is prepared by adding to a solution at -78 ° C in tetrahydrofuran, 4-aminoindole of lithium hexamethyldisilazide and dimethylcarbamyl chloride, followed by heating to room temperature, aqueous work, and chromatography on silica gel.
Step 2: Dimethyl amide of 4- (N, N-dimethylaminocarbonylamino) -indol-3-carboxylic acid. The desired compound is prepared according to the method of Indole 1, with the exception that 4- (N, N-dimethylaminocarbonylamino) indole, prepared as in Step 1, is used to replace the 6- (4-fluorophenylindole).
Step 3; Dimethyl amide of 4- (NN-dimethylamino-carbonylamino) -3- (4- (lH-2-methylimidazor4,5-clpyrid-1-yl) methyl-piperidin-1-in-carbonyl-indole-1-carboxylic acid) The desired compound is prepared according to the method of Example 6, with the exception that 4- (N, N-dimethylaminocarbonylamino) indole-3-carboxylic acid dimethyl amide, prepared as in Step 2, is used to replace the dimethyl amide of 6- (4-fluorophenyl) indole) -3-carboxylic acid.
The compounds represented in Table 3 are prepared from 6- (4-fluorophenyl) -3-. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) methyl-piperidin-1-yl] -carbonyl} indole by the methods described in Example 8 and in International Publication Number WO 93/1813.
Table 3
Example R2 38 -CH3
42 O NH2 44 H, C- or 50 -OH
51, NH2
52 < ^^ NS02CH3
56 ^ v ^ C02H
57 H
T? 58, CN
59, C02H
60 or NHCH3
62 -. 62 -SO2CH3
63 -. 63 -SO2CH2CH3
64 -. 64 -SO2C6H5
65 -. 65 -SQ2N (CH3) 2
Claims (9)
1. A compound of the Formula: or a pharmaceutically acceptable salt thereof, wherein R1 is one or more groups independently selected from the group consisting of: (a hydrogen, (b halogen, (c hydroxy, (d cyano, (e alkyl from one to six carbon atoms, (f alkenyl of 2 to 6 carbon atoms, (g alkynyl of two to six carbon atoms, (h alkoxy of one to six carbon atoms, (i alkanoyl of one to seven carbon atoms, -COOR7, wherein R7 is hydrogen, alkyl of one to ten carbon atoms, or phenylalkyl, wherein the alkyl portion is one to four carbon atoms, (k) unsubstituted phenyl, (1) phenyl, substituted with alkyl from one to six carbon atoms, alkoxy of one to six carbon atoms, halogen, -NR8R9, wherein R8 and R9 are independently selected from hydrogen and alkyl of one to six carbon atoms, or R8 and R9 together with the nitrogen atom with which they are bound form a pyrrolidinyl ring or, piperidinyl, piperazinyl, or morpholinyl, -COOR7, -C (0) NR8R9, or -S02NR8R9, (m) -C (0) NR8R9, (n) -0C (0) NR8R9, (o) -NHC (0) ) NR8R9, (p) 2- or 3-furyl, (q) 2- or 3-thienyl, (r) 2-, 4-, or 5-thiazolyl, (s) 2-, 3, or 4-pyridyl, (t) 2-, or 4-pyrimidyl, (u) phenylalkyl, wherein the alkyl portion is from one to six carbon atoms, (v) phenyl-alkyl, wherein the alkyl portion is from one to six atoms of carbon, and the phenyl fraction is substituted with halogen, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms, (w) unsubstituted benzoyl, (x) benzoyl substituted with halogen, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms, (and) unsubstituted phenoxy, (z) phenoxy substituted by halogen, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms, (aa) ) unsubstituted phenylalkyloxy, wherein the alkyl portion is from one to six carbon atoms or, (bb) phenylalkyloxy, wherein the alkyl portion is from one to six carbon atoms, and the phenyl moiety is substituted with halogen, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms unsubstituted (ce) phenyl-alkanoyl, wherein the alkanoyl portion is from one to seven carbon atoms, and (dd) phenylalkanoyl, wherein the alkanoyl portion is from one to seven carbon atoms, and the phenyl fraction is substituted with halogen, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms. R2 is selected from the group consisting of: (a) hydrogen, (b) alkyl of one to six carbon atoms; (c) - (CH2) pC00R7, where p is 0, 1, 2, 3 or 4, (d) - (CH2) qNR8R9, where q is 2, 3 or 4, (e) - (CH2) pCOR7 , (f) - (CH2) qOR7, (g) - (CH2) pS02R7, (h) - (CH2) pS02NR8R9, (i) - (CH2) pCONR10R?: L, wherein R10 and R11 are independently selected from of the group consisting of hydrogen, alkyl of one to six carbon atoms, - (CH2) rC007, wherein r is 1, 2, 3, or 4, - (CH2) rNR8R9, - (CH2) rOH, - (CH2 ) rS02R7, and - (CH2) rS02NR8R9, or R10 and R11 taken together define a pyrrolidine, morpholine, or thiomorpholine ring, (j) - (CH2) pCN, (k) - (CH2) p-lH-tetrazole-5 -yl, (1) -CONHNH2, (m) unsubstituted phenylalkyl, wherein the alkyl portion is one to carbon atoms, and (n) phenylalkyl, wherein the alkyl portion is from one to four carbon atoms, and the phenyl moiety is substituted with halogen, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms. R3 is selected from hydrogen and alkyl of one to six carbon atoms, and is selected from the group consisting of > C = 0, and > S (0) t, where t is 1 or 2, and W is CH or N; Z is CH or N. R4 is selected from the group consisting of: (a) alkyl of one to six carbon atoms, (b) alkenyl of two to six carbon atoms, (c) alkynyl of two to six atoms carbon, (d) alkoxy of one to six carbon atoms, (e) thioalkyl of one to six carbon atoms, (f) alkoxyalkyl, wherein the alkoxy and alkyl portions are independently from one to six carbon atoms, (g) alkylthioalkyl, wherein the alkyl portions are independently from one to six carbon atoms, (h) haloalkyl from one to six carbon atoms, (i) unsubstituted phenylalkyl, wherein the alkyl portion is from one to six carbon atoms. carbon, (j) phenylalkyl, wherein the alkyl portion is from one to six carbon atoms, and the phenyl is substituted with alkyl of one to six carbon atoms, haloalkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, six carbon atoms, hydroxy or halogen, (k) cycloalkyl of three to eight carbon atoms, (1) unsubstituted thiophenyl, and (m) thiophenyl substituted with alkyl of one to six carbon atoms, haloalkyl of one to six carbon atoms carbon, alkoxy of one to six carbon atoms no, hydroxy, or halogen. R5 and R6 are independently selected from the group consisting of hydrogen, alkyl of one to six carbon atoms, halogen, haloalkyl and alkoxy of one to six carbon atoms, m is 0 or 1, and n is 0, 1 or 2 , in the understanding that when Z is nitrogen, n can not be zero or one.
2. A compound or a pharmaceutically acceptable salt thereof, as defined in claim 1, wherein R1 is one more groups independently selected from the group consisting of: hydrogen, halogen, alkyl of one to six carbon atoms, alkynyl of two to four carbon atoms, alkoxy of one to six carbon atoms, unsubstituted phenyl, phenyl, substituted by alkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, or halogen, -COOR7, in wherein R7 is hydrogen, alkyl of one to ten carbon atom, or phenylalkyl, wherein the alkyl portion is one to four carbon atom, -C (0) NR8R9, -OC (0) NR8R9, 2- or 3 -furyl, and 2- or 3-thienyl; R3, R5 and R6 are hydrogen; And it's > C = 0 or > S (0) 2; and R 4 is alkyl of one to six carbon atoms.
3. A compound or a pharmaceutically acceptable salt thereof, as ded in claim 2, wherein: R2 is selected from the group consisting of: -CONR10R?: L, wherein R10 and R11 are independently selected from of the group consisting of: hydrogen, alkyl of one to six carbon atoms, and - (CH 2) gOR 7, wherein q is 2, 3 or 4, and R 7 is alkyl of one to four carbon atoms.
4. A compound or a pharmaceutically acceptable salt thereof, as ded in claim 3, wherein it is N.
5. A compound or a pharmaceutically acceptable salt thereof, as ded in claim 4, wherein Z is CH; m is 0 or 1; and n is 0 or 1, provided that m and n are both 0 or 1.
6. A compound or a pharmaceutically acceptable salt thereof, as ded in claim 5, wherein W and Z are CH.
7. A compound or a pharmaceutically acceptable salt thereof, as ded in claim 1, selected from the group consisting of: dimethyl amide of 6- (4-fluorophenyl) -3- acid. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) piperidin-1-yl] carbonyl} indole-1-carboxylic acid, 6- (4-fluorophenyl) -3-. { [4- (lH-2-methylimidazo [4.5- c] pyr id-1-l) piperidin-1-yl] carbonyl} indole, 3-. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) piperidin-1-yl] carbonyl} indole, 4-methyl ester of 1-dimethyl amide of 3- acid. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) piperidin-1-yl] carbonyl} indol-l, 4-dicarboxylic, 4-methyl ester of amide 1-dimethyl of acid 3-. { [4- (lH-2-methylimidazo [4.5-c] pyr id-1-yl) methylpiper idin-1-yl] carbonyl} indole, 4-dicarboxylic acid, dimethyl amide of 6- (4-fluorophenyl) -3- acid. { [4- (lH-2-methylimidazo [4.5-c] pyr id-1-yl) methylpiper idin-1-yl] carbonyl} indole-l-carboxylic acid, dimethyl amide of 4-chloro-3- acid. { [4- (1H-2-methylimidazo [4.5-c] pyrid-1-yl) methylpiperidin-1-yl] carbonyl} Indole-l-carboxylic acid, 1- (2-ethoxyethyl) -6- (4-fluorophenyl) -3-. { [4- (lH-2-methylimidazo [4.5-c] pyrid-1-yl) methylpiperidin-1-yl] carbonyl} indole, 1- (2-ethoxyethyl) -4-chloro-3-. { [4 - (1 H-2-methylimidazo- [4,5-c] pyrid-1-yl) methylpiperidin-1-yl] carboni 1} indole, 4-methyl ester of 1-dimethyl amide of 3- [-] acid. { 4- [2- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) ethyl] piperazin-1-yl} carbonyl] indole-1, 4-dicarboxylic acid, dimethyl amide of 6- (4-fluorophenyl) -3- [. { 4- [2- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) ethyl] piperazin-1-yl} carbonyl] indole-1, 4-dicarboxylic acid, tertiary butyl ester of 6- (4-fluorophenyl) -3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] sulfonyl} indole-1-carboxylic acid, 6- (4-fluorophenyl) -3-. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] sulfonyl} indole, dimethyl amide of 6- (4-fluorophenyl) -3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] sulfonyl} indole-1-carboxylic acid, tertiary butyl ester of 6- (4-fluorophenyl) -3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) methylpiperidin-1-yl] sulfonyl} indole-1-carboxylic acid, 6- (4-fluorophenyl) -3-. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) methylpiperidin-1-yl] sulfonyl} indole, dimethyl amide of 6- (4-fluorophenyl) -3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) ethylpiperidin-1-yl] sulfonyl} indole-l-carboxylic acid, dimethyl amide of 6- (4-fluorophenyl) -3- [. { 4-2- (1 H-2-methylimidazo- [4,5-c] pyrid-1-yl) ethyl] piperazin-1-yl} sulfonyl] indole-1-carboxylic acid, 6- (4-fluorophenyl) -3-. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole, dimethyl amide of 6- (4-fluorophenyl) -3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole-l-carboxylic acid, methyl ester of 3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole-4-carboxylic acid, 4-methyl-amide-1-dimethyl ester of 3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole-1, 4-dicarboxylic acid, l- (2-ethoxyethyl) -3- methyl ester. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole-l-carboxylic, 4-chloro-3-. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole, 1- (2-ethoxyethyl) -4-chloro-3-. { [4- (1H-2-ethylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole, dimethyl amide of 4-chloro-3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole-l-carboxylic acid, 4-methyl-3-. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole, 1- (2-ethoxyethyl) -4-methyl-3-. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole, dimethyl amide of 4-methyl-3- acid. { [4- (1H-2-methylimidazo- [4,5-c] pyrid-1-yl) piperidin-1-yl] acetyl} indole-1-carboxylic acid, 3-dimethyl amide of 3-acid. { [trans -4- [(1H-2-methyl imidazo- [4,5-c] pyrid-1-yl) methyl-1-cyclohex-1-yl] carbonyl} indole-1, 4-dicarboxylic.
8. A pharmaceutical composition useful for inhibiting platelet activating factor in a mammal in need of such treatment, which comprises an effective inhibitory amount of platelet activating factor to a compound as defined in claim 1, in combination with a pharmaceutically vehicle acceptable.
9. A method for the treatment of disorders mediated by platelet activating factor, which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of a compound as defined in claim 1.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/424,911 US5567711A (en) | 1995-04-19 | 1995-04-19 | Indole-3-carbonyl and indole-3-sulfonyl derivatives as platelet activating factor antagonists |
US08424911 | 1995-04-19 | ||
PCT/US1996/004010 WO1996033196A1 (en) | 1995-04-19 | 1996-03-25 | Indole-3-carbonyl and indole-3-sulfonyl derivatives as platelet activating factor antagonists |
Publications (2)
Publication Number | Publication Date |
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MX9708032A MX9708032A (en) | 1997-11-29 |
MXPA97008032A true MXPA97008032A (en) | 1998-07-03 |
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